Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[N-:6]=[N+:7]=[N-:8].[Na+].CN(C=O)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][C@H:24]1OS(C)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O>[N:6]([C@H:28]1[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:27]1)=[N+:7]=[N-:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 26.6 %

Procedure:
Sodium acetate (204 mg) and sodium azide (161 mg) were added to a DMF (5 mL) solution containing (trans)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((methylsulfonyl)oxy)piperidin-1-carboxylate (532 mg), followed by stirring at 80° C. for 4 hours. The pH of the reaction solution was adjusted to pH 12 with the addition of water and a 2M sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a white solid of (cis)-benzyl 3-azido-4-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate (124 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl.O1CCOCC1>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[NH2:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC1c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 198.2 %

Procedure:
tert-Butyl 2-(4-chlorophenyl)cyclopropylcarbamate (51.9 mg, 0.1938 mmol) was dissolved in Dichloromethane (1 ml) and 4M HCl solution in dioxane (0.4846 ml, 1.938 mmol) was added. The mixture was stirred for 3 hours at ambient temperature, during which time a white solid precipitated out of solution. The crude mixture was concentrated and chased with EtOAc (2×10 ml). The residual fine solid was dried under high vacuum to provide 39.2 mg of the title compound as a solid (99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH:42]=O)[CH:33]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:42][C:34]6[CH:33]=[N:32][C:41]7[C:36]([CH:35]=6)=[CH:37][CH:38]=[CH:39][CH:40]=7)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4cnc6ccccc6c4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and quinoline-3-carbaldehyde (72.9 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 27.8% yield, 34 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37]OS(C)(=O)=O)=[CH:6][C:5]=1[O:43][CH:44]([CH3:46])[CH3:45].[N-:48]=[N+:49]=[N-:50].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:14]=2[CH2:36][CH2:37][N:48]=[N+:49]=[N-:50])=[CH:6][C:5]=1[O:43][CH:44]([CH3:46])[CH3:45]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
The mesylate from Step 5 (0.115 g, 0.17 mmol) was dissolved in DMF (5 mL). NaN3 (0.065 g, 1.0 mmol) was added and the mixture was heated to 60° C. and stirred for three hours. Reaction was cooled to room temperature and water was added. Extracted with EtOAc and washed organic layer with brine. Dried organics over sodium sulfate and filtered and concentrated by rotary evaporation. Dried further under a strong vacuum. Obtained 0.100 g of 4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in 94% yield.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][NH2:38].CO>C(O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([NH:38][CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(Cl)nc2ccccc2c1-c1ccccc1
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNc1nc2ccccc2c(-c2ccccc2)c1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
To a solution of the compound obtained in Example 269 (100 mg) in ethanol (4 ml) was added 40% MeNH2 -methanol (12 ml), and the mixture was stirred for 4 hours with heating under reflux. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to yield the title compound as colorless crystals (65 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2ccc(F)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(F)cc2N1CCCCl
Yield: 77.5 %

Procedure:
6-Fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b) (0.090 g, 0.54 mmol), Cs2CO3 (0.263 g, 0.81 mmol) and 3-chloro-1-iodopropane (0.121 g, 0.59 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (8173MF55b) (0.102 g, 78%). 1HNMR(CDCl3) δ 6.95-6.91 (m, 1H), 6.82-6.78 (m, 11H), 6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.19-2.11 (m, 2H); 13CNMR(CDCl3) δ 164.6, 158.6 (d, J=240.7 Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5 Hz), 118.0 (d, J=9.3 Hz), 110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz), 67.8, 42.3, 39.3, 30.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](Cl)=[O:31].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ccccc1C=CC(=O)Cl
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: Cc1ccccc1C=CC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 41.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-methylcinnamic acid chloride (0.114 mmol), the title compound (18 mg, yield 41%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: N[N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.[O:12]=[C:13]1[CH2:18][C:17](=O)[CH2:16][CH2:15][NH:14]1>C(O)C>[CH2:3]1[N:2]2[C:17]3[CH2:16][CH2:15][NH:14][C:13](=[O:12])[C:18]=3[C:8]3=[CH:9][CH:10]=[CH:11][C:6](=[C:7]23)[O:5][CH2:4]1
Reactant: O=C1CCNC(=O)C1
Reactant: NN1CCOc2ccccc21
Solvent: CCO
Product: O=C1NCCc2c1c1cccc3c1n2CCO3
Reaction time: 2 h
Yield: 197.4 %

Procedure:
A solution of 4-amino-3,4-dihydro-2H-1,4-benzoxazine (1.0 g) and 2,4-dioxopiperidine (753 mg) in absolute ethanol (40 ml) was stirred under nitrogen for 1.5 h. The solvent was removed in vacuo and the residue was dissolved in diethylene glycol (30 ml) and heated at 100° for 1 h, then at 150° for 2 h. The solution was allowed to cool, poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined, dried organic extracts were evaporated to give a semi-solid (ca. 3 g) which was purified by FCC eluting with System A (400:10:1) to give the title compound (740 mg) as a solid, m.p. 298°-300°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11]>C1(C)C(C)=CC=CC=1>[OH:11][CH:10]([C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: Nc1ccccc1S
Solvent: Cc1ccccc1C
Product: OC(c1ccccc1)c1nc2ccccc2s1

Procedure:
A mixture of o-aminothiophenol (23.5 g) and dl-mandelic acid (25 g) was refluxed in xylene with a Dean-Stark tube for two days.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(OC(C)C)c1
Yield: 64 %

Procedure:
A mixture of 23 g (150 mmol) of 5-methyl-2-nitrophenol 28.1 g (1.1×150 mmol) of 2-iodopropane and 22.8 g (1.1×150 mmol) of anhydrous potassium carbonate in 150 ml of acetonitrile is stirred and refluxed for 18 hours overnight. The solids were removed, the solvent evaporated and the residue is taken up in diethyl ether and the solution washed with 50 ml of 2N potassium hydroxide (2X), brine, dried (magnesium sulfate), and evaporated to an oil. Distillation gives 18.6 g (64%) of 5-methyl-1-(1-methylethoxy)-2-nitrobenzene; bp 98°-100° C. at 0.5 mm.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.[CH3:21]C(=NO)C(=O)CC.CC1C=C(C=CC=1C)C=O>>[CH3:21][C:18]1[CH:19]=[C:14]([C:5]2[O:6][C:7]([CH2:8][CH3:13])=[C:3]([CH2:2][I:1])[N:4]=2)[CH:15]=[CH:16][C:17]=1[CH3:20]
Reactant: CCC(=O)C(C)=NO
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: Cc1ccc(C=O)cc1C
Product: CCc1oc(-c2ccc(C)c(C)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 3,4-dimethylbenzaldehyde gave 2-(3,4-dimethylphenyl)-5-ethyl-4-iodomethyloxazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([NH2:22])=[CH:17][N:16]=1.C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:18]([NH2:22])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)ncc2N)CC1
Yield: 88.8 %

Procedure:
1-t-Butoxycarbonyl-piperazine (2.36 g) was condensed with 2,4-dichloro-pyrimidin-5-ylamine (2.0 g) in dimethylsulfoxide (20 ml) in the presence of triethylamine (5.3 ml) according to the method described in Example 1, Step A. 4-(5-Amino-2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.4 g) was obtained as violet crystals. MS (ES+) 314/316 (M+H+). The title product (120 mg) was obtained from this intermediate according to the methods described in Example 1, step C and D. 2-Chloro-N-(2-chloro-4-{4-[(E)-3-(4-trifluoromethoxy-phenyl)-allyl]-piperazin-1-yl}-pyrimidin-5-yl)-isonicotinamide. M.p. 210-211° C.; 1H NMR (400 MHz, CDCl3) 2.5 (m, 4H), 3.1 (d, J=9 Hz, 1H), 3.6 (m, 4H), 6.1 (dt, J=18, 9 Hz, 1H), 6.4 (d, J=18 Hz, 1H), 7.1 (d, J=11 Hz, 2H), 7.3 (d, J=11 Hz, 2H), 7.6 (d, J=5 Hz, 1H), 7.7 (s, 1H), 7.8 (s, 1H, NH), 8.4 (s, 1H), 8.5 (d, J=5 Hz, 1H); MS (ES+) 553/555 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:37]I>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:31]([F:33])([F:32])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([N:20]([CH3:37])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CI
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)Cc1ccccn1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
In a solution of 0.35 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-234) synthesized similarly to Synthetic Example 5 in 20 ml of N,N-dimethylformamide, 0.04 g of 55% oily sodium hydride was added under cooling with ice with stirring, and stirred at the same temperature for 30 minutes. Then, 0.12 g of methyl iodide was added and thereafter the temperature was raised to room temperature, and continued to stir at the same temperature for further 2 hours. After the completion of the reaction, the reaction mixture was diluted with 80 ml of ethyl acetate, washed with water (50 ml×2), dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with high performance liquid chromatography that was eluated with acetonitrile-water (85:15) to obtain 0.25 g of the aimed product as colorless resinous substance.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(I)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.7 %

Procedure:
A mixture of 4-iodo-2-methylphenol (700 mg, 3.0 mmol), benzyl bromide (563 mg, 3.3 mmol), potassium carbonate (620 mg, 4.5 mmol), and acetonitrile (15 ml) was stirred at the ambient temperature for three days. The reaction was concentrated in vacuum and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 5% to 30% of ethyl acetate in heptane gave the target product as a colorless solid (950 mg, 98%). 1H NMR (500 MHz, CDCl3) δ 7.48 (d, 1H), 7.38-7.45 (m, 5H), 7.33-7.37 (m, 1H), 6.66 (d, J=8.54 Hz, 1H), 5.07 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C(O)C.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:30]3[CH:31]=[CH:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-c3ccc(N(C)C)cc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
Ethyl 5-bromo-N-(3,4dichlorobenzyl)indole-2-carboxylate (0.3 g), 4-dimethylaminobenzene boronic acid (0.13 g) and tetrakis triphenylphosphine-palladium(0) (20 mg) were dissolved in degassed toluene/ethanol/2M potassium carbonate (2:2:1) under argon and warmed at 80° C. for 16 hours. The reaction was then cooled to room temperature and partitioned between 2M HCl and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using i-hexane-15% ethyl acetate as eluent to give the desired end product as a pale brown solid (0.25 g, 76%); NMR δ(CDCl3) 1.38 (t, 3H), 2.98 (s, 6H), 4.38 (q, 2H), 5.78 (s, 2H), 6.80-7.80 (m, 11H); M/z (+) 467 (M+), 319, 280, 239.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:2]1.[F:27][C:28]1[N:29]=[N:30][C:31](F)=[CH:32][CH:33]=1.ClC1N=NC(Cl)=CC=1>>[F:27][C:28]1[N:29]=[N:30][C:31]([N:1]2[CH2:4][CH:3]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[CH:10][CH:9]=3)=[O:6])[CH2:2]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: Fc1ccc(F)nn1
Agent: Clc1ccc(Cl)nn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4ccc(F)nn4)C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 147A, substituting tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate and 3,6-difluoropyridazine for 3,6-dichloropyridazine.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N+:21]([O-:28])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>CCOCC.O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH:27]3[C:22]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH2:23][CH2:24][CH2:25][CH2:26]3)[N:21]([OH:28])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2C[N+]([O-])=C3CCCCC32)cc1OC
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2CN(O)C3(c4ccccc4)CCCCC23)cc1OC
Temperature: 35 °C
Yield: 23.6 %

Procedure:
A volume of 75 ml of 3 M phenylmagnesium bromide in ether was added over a period of five minutes to a warm (35° C) stirred solution of 41.25 g (0.015 mole) of 3,3a,4,5,6,7-hexahydro-3-(3,4-dimethoxyphenyl)-2H-indole-1-oxide in 500 ml of tetrahydrofuran. After stirring for 2 hours at room temperature, most of the THF was distilled off at atmospheric pressure. Ice water (1 liter) was added and the paste-like solid was filtered. The damp filter cake was added to 500 ml of 1N HCl. The taffy-like material which remained out of solution was added to 10 MKOH (300 ml). The mixture was extracted into 1.5 l methylenechloride and the extract was dried (K2CO3), charcoaled, filtered and concentrated. The residue was dissolved in 200 ml of petroleum ether. There was obtained 12.5 g (23.6%) of a white solid melting at 166°-168° C. Recrystallization from 2-propanol gave pure material melting at 168°-170° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][OH:25].O>C1COCC1.[H-].[Na+]>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])cn1
Yield: 49.5 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (25 g) and 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (32.1 g) in THF (250 ml), sodium hydride in oil (60%, 6.92 g) was added gradually while the solution was stirred under ice cooling conditions. The reaction mixture was stirred at room temperature for 15 more hours, after which it was added to water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residual crystal was collected by filtration and recrystallized from ethanol to yield 2-[2-(5-methyl-2-phenyl-4-oxazolyl]ethoxy]-5-nitropyridine (25.4 g, 49%) as a yellow-brown crystal.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].[I:21]Cl.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Reactant: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reaction time: 42 h
Yield: 93.4 %

Procedure:
To a solution of 5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (6.50 g) in mL glacial Acetic acid was added a solution of 9.205 g ICl (iodine monochloride) in 8 mL of acetic acid, with addition carried out at a rate such that the temperature of the resulting mixture did not exceed 24 degrees C. Water (11.0 mL) was added and the resultant mixture was stirred at 25 degrees C. for 42 hours. Excess ICl was decomposed by the addition of aqueous solution of sodium bisulfite (3.5 mL) at a rate such that the temperature of the reaction mixture did not exceed 20 degrees C. Water (40 mL) was added, and the precipitate was collected by filtration and air-dried to give 8.86 g of crude 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine. A suspension of the crude product in 90 mL water was made basic by addition of 50% NaOH, and the resulting solution was extracted into warm EtOAc. The combined organic layers were filtered and EtOAc was replaced by isopropanol via distillation. To the hot isopropanol solution was added 3.4 mL of 6N HCl and the resultant mixture was cooled slowly to 15 degrees C. Crystals of the resulting HCl salt were isolated by filtration, rinsed with isopropanol, and dried under vacuum at 70 degrees C. to give 6.08 g (58.8%) of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine hydrochloride salt, m.p.=262.0-263.0° C., MS (M+H)=401.