Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=O)[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32[O:28][CH2:27][CH2:26][O:25]3)[CH2:6]1)(=O)C.[NH2:29][OH:30].[OH-].[Na+].Cl.NO>C(O)C>[CH2:26]1[CH2:27][O:28][C:14]2([CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([C:18](=[N:29][OH:30])[CH2:17][C@:15]23[CH3:16])[C@:20]2([CH3:23])[C@H:7]([CH2:6][C@H:5]([OH:4])[CH2:22][CH2:21]2)[CH2:8][CH2:9]4)[O:25]1
Reactant: NO
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@@]2(C)[C@H]3CCC23OCCO3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2C(=NO)C[C@@]2(C)[C@H]1CCC21OCCO1

Procedure:
3α-Acetoxy-17,17-ethylenedioxy-5α-androstan-11-one (1.0 g) was added to a solution of hydroxylamine prepared by addition of 50% aqueous sodium hydroxide (4 ml) to hydroxylamine hydrochloride (2 g) in ethanol (30 ml). After 17 hours reflux most of the solvent was evaporated in vacuo, the residue was diluted with water and the solid (836 mg) was collected by filtration. A portion was recrystallized from aqueous ethanol to afford the title compound m.p. 158°-159°.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]1[CH:35]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:36][CH:37]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[CH2:31][CH:32]([OH:34])[CH2:33][N:29]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:39][CH:40]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above procedure Linoleic acid (2.80 g, 10.5 mmol) was coupled with the amine 100 (6.10 g, 11.45 mmol) using HBTU (4.55 g, 1.2 eq.) and DIEA (5.21 mL, 3.00 eq). After work-up and column purification the pure amide 102g was isolated as pale yellow gummy liquid (Yield, 6.10 g, 78%). 1H NMR (DMSO-d6, 400 MHz) δ=7.71-7.67 (m, 1H), 7.33-7.25 (m, 4H), 7.23-7.13 (m, 5H), 6.87-6.80 (m, 4H), 5.35-5.24 (m, 4H), 4.97 (d, J=3.90 Hz, 1H), 4.88 (d, J=3.90 Hz, 1H), 4.39-4.05 (m, 2H), 3.72 (s, 6H), 3.58-3.41 (m, 1H), 3.32-3.12 (m, 2H), 3.01-2.93 (m, 3H), 2.72-2.67 (m, 2H), 2.20-1.80 (m, 9H), 1.46-1.08 (m, 23H), 0.83 (t, J=6.34 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=176.63, 170.97, 170.86, 162.22, 158.09, 157.97, 145.07, 144.73, 135.87, 135.73, 135.48, 135.43, 129.60, 129.57, 129.55, 127.81, 127.71, 127.57, 127.55, 126.69, 126.53, 113.15, 113.07, 113.06, 85.79, 85.12, 68.61, 67.47, 63.36, 55.07, 55.01, 54.96, 54.93, 38.60, 38.56, 38.29, 38.18, 38.02, 36.30, 36.16, 36.01, 35.71, 34.17, 32.55, 30.70, 29.06, 29.02, 27.73, 27.70, 27.53, 26.08, 26.04, 24.49, 24.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([S:9][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:3][C:2]=1[F:1]
Reactant: FC(F)(F)CCI
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(SCCC(F)(F)F)cc1F
Temperature: 140 °C

Procedure:
To 3.4 mmol 3,4-difluoro-thiophenol and 5.1 mmol 1-iodo-3,3,3-trifluoropropane in 5 ml acetone was added 3.7 mmol potassium carbonate, and the mixture heated at 140° C. for 3 h under microwave irradiation. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo to afford the title compound. MS (m/e): 243.1 (M+H+, 100%)
Reaction SMILES: [C:1]([S-:3])#N.[K+].[C:5]([NH:12][C@H:13]([C:17]([N:19]1[CH2:24][CH2:23]C=[CH:21][CH2:20]1)=[O:18])[CH:14]([CH3:16])[CH3:15])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>O.CCO>[S:3]1[CH:1]2[CH:21]1[CH2:20][N:19]([C:17](=[O:18])[C@@H:13]([CH:14]([CH3:15])[CH3:16])[NH:12][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:24][CH2:23]2
Reactant: N#C[S-]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CCC1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC2SC2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2.91 g of KSCN in 3 ml of H2O are added to a mixture of 5.96 g of 3,4-epoxy-N—(N-BOC-valyl-1,2,5,6-tetrahydropyridine in 10 ml of absolute EtOH and the mixture obtained is stirred for 72 hours at RT. The mixture obtained is subjected to aqueous extraction, the solvent of the organic phase obtained is evaporated and the evaporation residue is subjeted to chromatography. 3,4-Epithio-N(N-BOC-(R)-valyl)-piperidine is obtained. Melting point: 69.71°
Reaction SMILES: Cl.C[O:3][C:4](=[O:36])[C@@H:5]([NH:15][C:16](=[O:35])[C@@H:17]([NH:28][C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[OH-].[Li+]>O.C1COCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][C@H:5]([NH:15][C:16](=[O:35])[C@@H:17]([NH:28][C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:27])=[CH:23][CH:24]=1)[C:4]([OH:36])=[O:3])([CH3:14])([CH3:12])[CH3:13]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 2-(S)-[2-(S)-allyloxycarbonylamino-3-(4-carbamimidoyl-phenyl)-propionylamino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride (3.06 g, 5.8 mmol) in 100 ml of water and 30 ml of THF was added lithium hydroxide hydrate (0.49 g, 11.6 mmol). The solution was stirred at room temperature for 12 hours, evaporated, and freeze-dried. The residue was purified by chromatography on Sephadex LH20 employing n-butanol/glacial acetic acid/water (17/1/2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water, and the aqueous solution was freeze-dried. Yield: 2.7 g (97%). MS: m/z=477.4 (M+H)+.
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][NH2:22]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:18]([Cl:17])[CH:19]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2ccc(Cl)c(Cl)c2)c(=O)c1=O
Yield: 42 %

Procedure:
A solution of 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5 mmol, Example 10) and 3,4-dichlorobenzylamine (0.880 g, 5.0 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for approximately 96 hours. The residue isolated after removal of solvent was recrystallized from N,N-dimethylformamide (twice) and from 2-methoxyethanol to provide 0.687 g (42%) of the title compound as a white solid: mp 302°-303° C.; 1H NMR (DMSO-d6) δ 7.77 (m, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 7.33 (m, 1H), 4.71 (d, 2H), 1.35 (s, 9H) ppm. IR (KBr): 3450, 3230, 1800, 1650 cm-1. MS (m/z) 326/328/330 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid (3.0 g) in methanol (30 mL) was added conc. sulfuric acid (3 mL), and the mixture was heated for 5 hours under reflux. The reaction solution was allowed to stand for cooling down to room temperature, and then concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.99 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[CH:16]([CH3:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]=3[CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.[Cl-:26].[Cr+3:27].[Cl-].[Cl-]>C1COCC1>[Cl-:26].[Cl-:26].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3([Cr+2:27])[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]3[CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [Cr+3]
Reactant: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Cr+2])(c2cccc3ccc(C)nc23)C(C)=C1C
Reaction time: 2 h
Yield: 50 %

Procedure:
0.3 g of 1-(2-methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene (1.14 mmol) in 30 ml of THF was deprotonated using 0.45 ml of n-butyllithium (2.5 M in hexane, 1.14 mmol). After the mixture had been stirred for two hours, the red solution was added dropwise to a suspension of chromium(III) chloride in 20 ml of THF. After the mixture had been stirred at room temperature for 16 hours, the solvents were evaporated off, and the resultant residue was taken up in 20 ml of toluene. The green suspension was filtered, and the residue was extracted a number of times with hot toluene. Conventional work-up gave the product as a green powder (0.22 g) in a yield of 50%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH2:13]1[CH:22]2[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:14]2[CH2:15][CH2:16][CH:17]3[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13]2)=[N:3][N:4]=1
Reactant: C1CCC2CNCCC2C1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1nnc(N2CCC3CCCCC3C2)c2ccccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A resealable pressure bottle was charged with 1,4-dichlorophthalazine (1258 mg, 6.28 mmol), decahydroisoquinoline (588 μl, 3.95 mmol), potassium carbonate (546 mg, 3.95 mmol) and DMSO (20 mL, 0.2 M). Reaction was stirred at 80° C. for 16 h, then cooled to RT and diluted with 5 mL of DMSO. The solution was purified by Gilson HPLC (10% to 90% CH3CN/H2O/0.1% TFA) to afford 1-chloro-4-(octahydroisoquinolin-2(1H)-yl)phthalazine. MS [M+H]=302.1. Calcd for C17H20ClN3: 301.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[CH:14]=[O:15]>CC(N(C)C)=O>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:14]=[O:15]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COc1ccc(O)cc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(C=O)cc2F)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
4.9 g (40 mmol) of 4-methoxy-phenol and 4.4 ml (40 mmol) of 3,4-difluorobenzaldehyde were dissolved in 40 ml DMA and stirred in a microwave (CEM Explorer) for 15 minutes at 110° C., then filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. The residue was separated through a KG column with a gradient (cyclohexane+10-25% ethyl acetate) and concentrated by rotary evaporation.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ccn(Cc2ccc(F)cc2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4ccc(F)cc4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-fluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH2:24]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([O:16][C:15](=[O:17])[CH:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:23])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:35][CH:34]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
300 mg of 2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoic acid were dissolved in 10 ml of methylene chloride and to this solution, were added successively, 240 mg of benzyl-4-hydroxybenzoate and 116 mg of N,N-dimethylaminopyridine. The reaction mixture was cooled to 0° C. and 217 mg of 1,3-dicyclohexylcarbodiimide was added at once. The mixture was stirred at 0° C. for 2 hours then at room temperature for 2 hours. The reaction mixture was filtered and the resulting filtrate was washed with 2 portions of 25 ml of water. The organic phase was dried over MgSO4 and the solvent evaporated. The oil/solid residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes) and gave 403 mg of a colorless oil, 1H NMR (CDCl3): 8.07 (d, J=8.8 Hz, 2H), 7.38-7.50 (m, 4H), 7.27 (m, 3H), 7.15 (m, 1H), 7.08 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 3.73 (dd, J=9.0, 7.5 Hz, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.68 (s, 4H), 1.2-1.5 (m, 6H), 1.29 (s, 3H), 1.28 (s, 9H), 0.88 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][C:4]=1[O:18][CH3:19].Cl[Si](C)(C)C.BrCCBr.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>[Zn].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.C1COCC1>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Brc1ccccn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cc1ccccn1

Procedure:
A solution of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (320 mg, 1.0 mmol) and THF (10 mL) was treated with Zn powder (activated by grinding with mortar and pestle), a drop of chlorotrimethylsilane, and a drop of 1,2-dibromoethane. The mixture was heated at reflux for 1 h. The resultant organozinc reagent was filtered through a plug of Celite, and transferred to a flask containing 2-bromopyridine (360 mg, 2.0 mmol) and Pd(Ph3P)4 (115 mg, 0.1 mmol). The mixture was degassed with bubbling argon for 15 min, and heated at reflux for 12 h. The reaction was poured into H2O (40 mL) and extracted with CH2Cl2 (2×30 mL). The organic extracts were dried (MgSO4) and concentrated to afford a colorless solid. Purification of the solid by flash chromatography on silica gel (EtOAc:hexanes 3:1) afforded the desired 2-[3-methoxy-4-(pyridin-2-ylmethyl)phenyl]-1,3-benzoxazole as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.55 (d, 1H), 7.76–7.82 (m, 3H), 7.56–7.62 (d, 2H), 7.32–7.36 (m, 3H), 7.11–7.16 (m, 2H), 4.23 (s, 2H), 3.95 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:7]=1[C:8]#[N:9].CSC>ClCCCl>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:7]=1[CH2:8][NH2:9]
Reactant: N#Cc1cc(Cl)ccc1OCc1ccccc1Br
Solvent: ClCCCl
Solvent: CSC
Product: NCc1cc(Cl)ccc1OCc1ccccc1Br
Temperature: 65 °C
Yield: 60 %

Procedure:
To a stirred solution of 2-(2-Bromo-benzyloxy)-5-chloro-benzonitrile Example 348A (1.52 g, 4.71 mmol) in DCE (50 mL) under argon was added BH3 DMS (30.0 mL, 18.8 mmol). The reaction mixture was heated at 65° C. for 14 h and then cooled to room temperature. The mixture was quenched with 1N HCl solution slowly (25 mL). This solution was then mixed with 1N NaOH solution (30 mL), and extracted with EtOAc (3×80 mL). The combined EtOAc extracts were washed with saturated NaHCO3 solution (1×40 mL) and brine (1×40 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 0.92 g (60%) of crude 2-(2-Bromo-benzyloxy)-5-chloro-benzylamine Example 348B which was used as is without further purification. HPLC Rt=2.87 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=326
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:7]([CH2:15][CH:16]=[CH2:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>CN(C)C1C=CN=CC=1.ClCCl.C(=O)([O-])O.[Na+]>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:1][CH2:2][CH:3]([N:7]([C:8]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:14])[CH2:15][CH:16]=[CH2:17])[CH2:4][CH:5]=[CH2:6])=[O:33])=[CH:35][CH:36]=1)([O-:27])=[O:26]
Reactant: C=CCC(CO)N(CC=C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC(COC(=O)c1ccc([N+](=O)[O-])cc1)N(CC=C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a mixture of tert-butyl [1-(hydroxymethyl)but-3-en-1-yl]prop-2-en-1-ylcarbamate (15.0 g) produced above, triethylamine (19.0 g) and dichloromethane (150 mL) was added N,N-dimethylpyridin-4-amine (0.7 g). To the mixture was added dropwise a solution of 4-nitrobenzoyl chloride (14.2 g) in dichloromethane (30 mL), and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, the mixture was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (14.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:25]=[CH:24][C:15]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]=2[N+:26]([O-:28])=[O:27])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-amino-3-nitrobenzophenone and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.61 (bs, 1H), 9.12 (d, J=8.7, 1H), 9.06 (d, J=2.4, 1H), 8.79 (d, J=1.8, 1H), 8.28-8.25 (m, 1H), 8.23-8.19 (m, 1H), 7.82-7.81 (m, 1H), 7.80-7.79 (m, 1H), 7.67-7.64 (m, 1H), 7.58-7.53 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7](=[O:16])[C:6]([C:17]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])=[C:5]2[OH:28]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][CH2:14][CH2:15]1)[C:7](=[O:16])[C:6]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[C:5]2[OH:28]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A mixture of 1,1-dimethylethyl N-((6′-chloro-4′-hydroxy-2′-oxo-2′H-spiro[cyclopentane-1,1′-naphthalen]-3′-yl)carbonyl)glycinate (0.2 g, 0.5 mmol) in 2 mL TFA was stirred at room temperature for 30 minutes, M+1=350. The mixture was concentrated and triturated in ether/hexane (10:1). The solid was filtered, washed with 10 mL ether/hexane (10:1), and dried under high vacuum to give 135 mg of the salt as an off-white solid. MS (m/z)=350 (M+H)+. Calculated for C17H16ClNO5 349.07.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][C:2]1=[O:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][C:2]1=[O:13]
Reactant: ClCCCCBr
Reactant: O=C1CCC(=O)c2ccccc2N1
Product: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Yield: 58.7 %

Procedure:
Analogously to the procedure described in Example 1, reaction of 3,4-dihydro-1H-1-benzazepine-2,5-dione (11.42 mmol, 2.00 g) and bromo-4-chlorobutane (13.7 mmol, 2.35 g) afforded 1.78 g of the title compound, contaminated with reactants to an extent of 30%. The mixture thus obtained was reacted without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>>[C:10]([CH2:12][C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)=[O:14])#[N:11]
Reactant: CCOC(=O)CC#N
Reactant: Cc1cc(N)ccc1F
Product: Cc1cc(NC(=O)CC#N)ccc1F
Temperature: 180 °C
Reaction time: 14 h
Yield: 93.7 %

Procedure:
A mixture of 4-fluoro-3-methylaniline (2.50 g, 20.0 mmol) and ethyl cyanoacetate (2.70 g, 24.0 mmol) was stirred at 180° C. for 14 hr. After cooling to room temperature, the obtained solid was washed with hexane and collected by filtration to give the title compound (3.60 g, 95%) as a brownish-red solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1ncc(N)c(OC)n1
Solvent: c1ccncc1
Product: COc1ncc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c(OC)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
5-Dimethylamino-1-naphthalenesulphonyl chloride (0.296 g) and 5-amino-2,4-dimethoxypyrimidine (0.155 g) were mixed together as solids. Pyridine (10 mls) was added and the solution was stirred at 0° C. for 30 minutes. The mixture was then heated at 80° C. for 5 hours. Volatile material was removed by evaporation and the residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 5-dimethylamino-N-(2,4-dimethoxy-5-pyrimidinyl)-1-naphthalenesulphonamide (0.28 g), m.p. 201° C.; 1H NMR (d6 -DMSO): 2.85 (s, 6H), 3.1 (s, 3H), 3.8 (s, 3H), 7.3 (d, 1H), 7.55 (q, 2H); 7.95 (d, 1H), 8.05 (s, 1H), 8.30 (d, 1H), 8.48 (d, 1H), 9.85 (s, 1H); mass spectrum (+ve CI): 389 (M+H)+.