Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH:40]=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH2:35]2)=[CH:30][C:29]=1[O:42][CH3:43]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5([CH:40]=[O:41])[CH:35]=[CH:36][CH:37]=[CH:38][CH2:39]5)=[CH:30][C:29]=4[O:42][CH3:43])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 86.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (2.3 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off and the solvent was evaporated to an oil. Purification was carried out by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2% methanol: 98% dichloromethane, 600 ml). The fractions containing the pure product were combined and concentrated to give 4.24 g (87%) of an off-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of 1-[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]phenylmethanone as off-white crystals, m.p. =128°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: CCS(=O)(=O)N1CCC(Nc2nn(COCC[Si](C)(C)C)c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A 10 ml round-bottomed flask equipped with a magnetic stirrer is charged with 50 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1-([2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.1 ml of TFA is added and the mixture is stirred at RT for 3 h. It is concentrated under RP and the solid obtained is taken up in 20 ml of water and extracted with three times 20 ml of AcOEt. The combined organic phases are dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and with a mixture of DCM and methanol (90/10 by vol.), to give 27 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (yellow solid). 1H NMR (400 MHz, DMSO-d6) 1.23 (t, J=7.3 Hz, 3 H) 1.63 (m, 2 H) 2.09 (m, 2 H) 2.97 (m, 2 H) 3.05 (q, J=7.3 Hz, 2 H) 3.61 (m, 2 H) 3.81 (m, 1 H) 6.23 (broad m, 1 H) 7.34 (t, J=7.8 Hz, 2 H) 7.70 (m, 1 H) 8.18 (broad s, 1 H) 8.27 (broad d, J=8.5 Hz, 1 H) 8.56 (d, J=8.5 Hz, 1 H) 13.07 (broad s, 1 H) LC-MS-DAD-ELSD: 497 (+)=(M+H)(+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([OH:12])=[CH:6][CH:5]=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[CH3:11]
Reactant: BrCCCCBr
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Product: Cc1[nH]c2ccc(OCCCCBr)cc2c1C

Procedure:
In analogy to example 3.1, 2,3-Dimethyl-1H-indol-5-ol [for preparation see for example: Roth, H. J.; Lepke, P. Synthesis of indole and carbazole derivatives by condensation of α-hydroxyketones and aromatic amines. Arch. Pharm. (Weinheim) (1972), 305(3), 159-71.] and 1,4-dibromobutane were converted to yield 5-(4-Bromo-butoxy)-2,3-dimethyl-1H-indole as white solid, mp 119-120° C., MS: 295 (M, 1Br).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Cl)[CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
100.0 mg of compound (6) was dissolved in 0.8 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 10 mg of sodium hydride under cooling with ice. After 15 minutes, 44 μl of hexyl chloride was added, and the reaction solution was stirred under cooling with ice for 2 hours. The reaction solution was allowed to react at room temperature for another 90 minutes under stirring. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×21 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 18.7 mg of compound (45) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7]O.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7][Br:17]
Reactant: OCc1ccc(F)cc1OCC(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(CBr)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorobenzyl alcohol (1.2 g, 5.3 mmol) from Step 2 above in ether (30 mL) was added CBr4 (3.0 g, 9.2 mmol) and triphenylphosphine (2.4 g, 9.2 mmol). The mixture was stirred at ambient temperature for 14 h. Triphenylphosphine oxide was removed by filtration and the filtrate was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressureized silica gel column chromatography using a gradient elution of 0-5% EtOAc:hexanes to give 2-(2,2,2-trifluoro-ethoxy)-4-fluorobenzyl bromide as a colorless oil (HPLC retention time=10.4 min (method A)).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:2].[CH:22](=O)[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]>C(O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[CH:22][C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25])[CH3:21]
Reactant: O=Cc1ccccc1O
Reactant: CCN(CC)c1ccc(C=Nc2ccccc2N)c(O)c1
Solvent: CCO
Product: CCN(CC)c1ccc(C=Nc2ccccc2N=Cc2ccccc2O)c(O)c1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a yellowish brown suspension of 0.3 g (1.06 mmol) N-Mono[4-(diethylamino)-salicylidene]-1,2-phenylenediamine from example 30 in 2 ml ethanol are added dropwise at 60° C. 129 mg (112 μl, 1.06 mmol) salicylaldehyde. The reaction solution is stirred for 5 hours at 75° C. and after cooling to room temperature concentrated to dryness. The crude product is resolved by column chromatography (n-hexane/ethyl acetate 65:35). Yield: 139 mg (34%). colourless oil.
Reaction SMILES: CN(C)[C:3]1[CH:8]=CC=C[CH:4]=1.C([O:13][C:14]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]2[C:15]=1[CH:16]=[C:17]([CH3:26])[C:18](=[O:25])[NH:19]2)C=C>CCCCCC>[CH2:8]([C:23]1[C:14]([OH:13])=[C:15]2[C:20](=[C:21]([CH3:24])[CH:22]=1)[NH:19][C:18](=[O:25])[C:17]([CH3:26])=[CH:16]2)[CH:3]=[CH2:4]
Reactant: C=CCOc1ccc(C)c2[nH]c(=O)c(C)cc12
Reactant: CN(C)c1ccccc1
Solvent: CCCCCC
Product: C=CCc1cc(C)c2[nH]c(=O)c(C)cc2c1O
Temperature: 200 °C
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
N,N-dimethylaniline (10 ml) was added to 5-allyloxy-3,8-dimethylcarbostyril (4.32 g, 18.9 mmol), and stirred for 2 hours and 40 minutes in a bath of 200° C. in the atmosphere of argon. After cooling, hexane was added. Precipitated crystals were collected by filtration, and purified by silica gel chromatography (chloroform:methanol =10:1). The purified product was subjected to recrystallization (chloroform-n-hexane) to obtain 3.86 g of the title compound as colorless crystals (89.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>>[CH3:13][N:14]([CH3:22])[C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][CH:16]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CN(C)c1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1nc(Nc2ccc(N(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol), 4-dimethylamino-aniline (136.2 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 222 mg (79.9%) of gray solids. 1H NMR (CDCl3): 7.82-7.70 (m, 3H), 7.62 (d, J=9.0 Hz, 2H), 7.45 (t, J=7.5 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 2.97 (s, 6H), 2.66 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[F:10].N1C=CC=CC=1.[C:53](OC(=O)C)(=[O:55])[CH3:54].Cl>C(Cl)Cl>[C:53]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[F:10])(=[O:55])[CH3:54]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of (R)—N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide hydrochloride (Example 269, 30 mg, 0.04 mmol) in DCM (2 mL) at rt was added pyridine (7.8 μL, 0.1 mmol) followed by acetic anhydride (4.6 μL, 0.05 mmol). The reaction mixture was stirred at rt for 1 h, then poured into 1N HCl and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by ISCO column chromatography (4 g, 0-50% EtOAc/hexane) to yield (R)—N-(1-(3-(acetamidomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 270) as a white foam (21 mg, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (dd, J=6.57, 2.02 Hz, 1H), 7.86 (dt, J=8.53, 2.18 Hz, 1H), 7.25 (m, 2H), 7.13 (m, 3H), 6.99 (m, 5H), 6.81 (s, 1H), 6.69 (m, 2H), 5.87 (m, 2H), 4.38 (m, 2H), 4.04 (d, J=13.14 Hz, 1H), 3.75 (d, J=13.14 Hz, 1H), 1.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 0 °C
Yield: 40.4 %

Procedure:
A mixture of 2,4-dichloropyrimidine (3.1 g, 20 mmol), 4-chlorophenylboronic acid (3.0 g, 20 mmol), and tetrakis(triphenylphosphine)palladium (0.69 g, 0.6 mmol) in dimethoxyethane (200 mL)/sat. Na2CO3 solution (34 mL) was heated to 80° C. for 20 h. The cooled mixture was poured into ice-water and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate/cyclohexane (1:2, v/v) as eluent to give the title compound (1.82 g, 40%) as white solid. NMR (DMSO-d6) δ 7.67 (d, 2H, J=7 Hz), 8.19 (d, 2H, J=5 Hz), 8.23 (d, 2H, J=7 Hz), 8.86 (d, 2H, J=5 Hz) ppm; mp 290-292° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1.C[Sn](C)(C)[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C1(C)C(C)=CC=CC=1.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>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[N:12]=[CH:11][C:10]([C:8]([C:6]2[CH:7]=[C:2]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:15][CH:14]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2ccncc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Yield: 31.9 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone (100 mg; 0.24 mmol), 4-trimethylstannylpyridine (115 mg; 0.47 mml) and PdCl2(PPh3)2 (50 mg; 0.07 mmol) are dissolved in xylene (2 ml) and refluxed under argon for 20 min. The reaction mixture is purified via chromatography (SiO2; acetone/hexanes 3/7) and yields the title compound as a colorless foam (32 mg; 32%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:13][N:11]1[CH:12]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:15][NH2:16])=[CH:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc(NN)nn2)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of 3-chloro-6-(1-methyl-1H-pyrazole-4-yl)-pyridazine (21.0 g, 108 mmol) in ethanol (370 mL) was added hydrazine monohydrate (36 mL). The reaction mixture was stirred at reflux for 18 h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide 18 g of [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine as a beige solid (87% yield): 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 4.28 (s, 2H), 7.02 (d, 1H), 7.59 (d, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.19 (s, 1H); MS (m/z) 191 [M+H+]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:19]=[C:18]([OH:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>C(Cl)Cl>[Br:1][C:19]1[C:10](=[O:9])[NH:11][C:12]2[C:17]([C:18]=1[OH:20])=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c(O)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.4 %

Procedure:
N-bromosuccinimide (2.21 g) was added to the solution of 2,4-dihydroxyquinoline (2 g) in DCM (50 ml). The mixture was stirred at room temperature for 3 days. The mixture was filtrated and the solid was triturated with isopropanol. After filtration, toluene was added to the solid and the solvent was evaporated under reduced pressure to give the desired product (1.92 g) as a beige solid. LRMS (ES+) m/z 240.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])[C:4]=1[OH:14].[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C.C(O)C>[C:15]([O:14][C:4]1[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:17])[CH3:16]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1cccc(C=C[N+](=O)[O-])c1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture of 2-methoxy-6-(2-nitrovinyl)phenol (29.0 grams, 0.15 mole) and sodium acetate (12.4 grams, 0.15 mole) in acetic anhydride (100 ml.) was refluxed for 4 hours and then poured into ice water. The resulting semi-solid precipitate was dissolved in hot 95% ethanol. Cooling the solution precipitated the crude product which was purified for analysis by chromatography on silica gel with methylene chloride as elutant. The purified 2-methoxy-6-(2-nitrovinyl)phenyl acetate melted at 128° - 129° C.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25]CC(O)=O)[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=4)[O:2]1.[CH2:30]1OC2C(=CC3C=C(C(O)=O)C4C(C=3C=2)=CC(OC)=CC=4)[O:31]1.N>>[CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@@H:22]4[CH2:30][OH:31])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([O:18][CH3:19])=[CH:10][CH:9]=4)[O:2]1
Reactant: COc1ccc2c(C(=O)O)cc3cc4c(cc3c2c1)OCO4
Reactant: COc1ccc2c(CNCCCCCC(=O)O)cc3cc4c(cc3c2c1)OCO4
Agent: N
Product: COc1ccc2c(CN3CCC[C@@H]3CO)cc3cc4c(cc3c2c1)OCO4

Procedure:
N-(2,3-Methylenedioxy-6-methoxy-phenanthr-9-ylmethyl)-6-aminohexanoic acid (21) General procedures a, b & c from 10 (78%); white powder; mp 167-169° C.; 1H NMR (400.13 MHz) δ 7.88 (d, J=4 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J=2 Hz, 1H), 7.44 (s, 1H), 7.13 (dd, J=4 Hz, 2 Hz, 1H), 7.05 (s, 1H), 5.99 (s, 2H), 3.87 (s, 2H), 3.82 (s, 3H), 2.75 (m, 2H), 2.23 (t, J=6 Hz, 2H), 1.53 (m, 2H), 1.44 (m, 2H), 1.28 (m, 2H); MS (DCI/NH3) m/e: 396 (M+H)+. Anal. (C23H25O5N) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH2:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Reactant: NCCCN1CCCC1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 56 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (15 mg, 0.0344 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.05 mL) was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 56% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.03 (t, J=5.6 Hz, 1 H), 8.50 (s, 1 H), 7.29-7.17 (m, 2 H), 7.20-7.16 (m, 2 H), 7.01-6.91 (m, 4 H), 6.69 (s, 1 H), 3.93 (s, 2 H), 3.44-3.32 (m, 6 H), 2.35 (t, J=8 Hz, 2 H), 2.04-1.96 (m, 2 H), 1.89-1.78 (m, 2 H); MS m/z 533 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]nc(I)c2c1
Reactant: Fc1cccnc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ncccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.291 g (23.921 mmol) of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 8.573 g (26.313 mmol) of caesium carbonate were put in DMF (10 ml) and then 5.00 g (26.313 mmol) of 2-(bromomethyl)-3-fluoropyridine dissolved in DMF (20 ml) was added dropwise. The mixture was stirred overnight at RT. Then it was left to cool and was poured into 200 ml water. A precipitate was filtered off with suction, it was washed with water and dried overnight under high vacuum. 6.28 g (70% of theor.) of the title compound was obtained.
Reaction SMILES: C(O[C:6]([N:8](C)[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:46])[C@@H:17]2[CH2:24][N:23]3[C:25]4[CH:26]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:28]=[CH:29][C:30]=4[C:31]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[C:22]3[C:21]3[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=3[O:19][CH2:18]2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:32]1([C:31]2[C:30]3[CH:29]=[CH:28][C:27]([C:38]([O:40][CH3:41])=[O:39])=[CH:26][C:25]=3[N:23]3[C:22]=2[C:21]2[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=2[O:19][CH2:18][C@H:17]([N:16]([CH3:46])[CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:9]([NH:8][CH3:6])[CH2:10]2)[CH2:24]3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN1CCC(N(C)C(=O)OC(C)(C)C)C1)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(CCN(C)[C@H]2COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)OC)cc4n3C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl (7R)-7-[(2-{3-[(tert-butoxycarbonyl)(methyl)amino]pyrrolidin-1-yl}ethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate was dissolved in DCM and treated with TFA. The solution was stirred for 2 h at RT. The solvents were removed in vacuo to leave the product as pale yellow foam. (ES+) m/z 545 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:25]([O-])([N+]([O-])=O)=[O:26]>>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CCCO1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CCCO1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 27.6 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-tetrahydrofurfuryl-3-(D-glucopyranosyl)urea and 6 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 1.1 g of 1-(2-chloroethyl)-1-nitroso-3-tetrahydrofurfuryl-3-(D-glucopyranosyl)urea are thereby obtained as yellow caramel.