Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:23]1([CH:22]=[C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)[C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cnc2[nH]c(C(=CC3CCCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 81.2 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclohexyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.24 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 12 h. The mixture was then diluted with ethyl acetate (150 mL) and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclohexyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (80 mg, 82.6%) as a white solid: LC/MS m/e calcd for C23H26N2O3S [M+H]+ 411.54, observed 411.2.
Reaction SMILES: [Cl:1]C(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[NH2:22][C@@H:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][N:25]([CH3:27])[CH3:26]>C(Cl)Cl>[ClH:1].[N:22]([C@@H:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][N:25]([CH3:27])[CH3:26])=[C:5]=[O:11]
Reactant: CN(C)C[C@@H](N)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@@H](N=C=O)c1ccccc1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) and stirred solution of triphosgene (27.1 g, 91.32 mmol) in DCM (250 mL) was drop wise added a solution of diisopropylethyl amine (23.6 g, 182.26 mmol) in DCM (50 mL) over a period of 20 min. A solution of N-[(2S)-2-amino-2-phenylethyl]-N,N-dimethylamine (54e, 15.0 g, 91.32 mmol) in DCM (100 mL) was drop wise added to the brown reaction mixture while maintaining the temperature below 10° C. The resulting reaction mixture was removed from cooling and stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum to a residue and stirred with 10% DCM in hexane (50 mL). The solid N-[(2S)-2-isocyanato-2-phenylethyl]-N,N-dimethylamine hydrochloride compound 54f was separated by filtration and used for the next reaction without further purification. (Note: The obtained solid product was stored under nitrogen). 1H NMR (300 MHz, dmso-d6): δ 3.29 (s, 3H), 3.38 (s, 3H), 3.68 (t, J=10.1 Hz, 1H), 4.42 (dd, J=11.5, 6.5 Hz, 1H), 5.35 (dd, J=9.6, 6.2 Hz, 1H), 7.4-7.6 (m, 5H).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)CC(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octyl-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octyl-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:26][C:23]1[C:22]([NH:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)CC(C)C)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)CC(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1-{4′-[3-Methyl-4-(3-methyl-butyrylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.060 g, 0.13 mmol) in MeOH and H2O was treated with lithium hydroxide (0.100 g, 2.4 mmol) and stirred at 60° C. for 1 hour. The mixture was submitted to standard workup to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
3-Bromo-4-chlorobenzoic acid (1.0 g, 4.24 mmol, 1.0 eq) was dissolved in dry DMF and stirred for 10 minutes. The solution was cooled to 0° C. and treated with N,O-dimethyl hydroxylamine hydrochloride (0.828 mg, 8.48 mmol, 2.0 eq), 1-hydroxybenzotrizole (860 mg, 6.36 mmol, 1.5 eq), N,N-diisopropyl ethylamine (820 mg, 6.37 mmol, 1.5 eq), and EDC HCl (1.2 g, 6.37 mmol, 1.5 eq). The reaction mixture was stirred for 12 h, evaporated under reduced pressure and diluted with water (25 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired product (1 g, 85%). 1H NMR (400 MHz, CD3OD) δ 3.34 (s, 3H), 3.57 (s, 3H), 7.47-7.49 (d, 1H), 7.71-7.74 (d, 1H), 7.85-7.88 (d, 1H). MS (ESI): 278.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1.CCOC(C)=O.C(Cl)(=O)C>[C:24]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2F)ccn1
Reaction time: 0.75 h
Yield: 132.6 %

Procedure:
A tert-butyl 4-(2-aminopyridin-4-yloxy)-3-fluorophenylcarbamate (150 mg, 0.47 mmol) in anhydrous pyridine (0.5 mL) was cooled to 10° C. and treated with acetyl chloride (33 μL, 0.47 nmol) and the mixture stirred for 45 min. An additional portion of acetyl chloride (16 μL, 0.24 mmol) was added to the reaction and stirring continued for 25 min. The mixture was diluted with EtOAc (20 mL), washed with brine, dried (MgSO4) and concentrated under vacuum to give the title compound (115 mg, 68%). 1H NMR (DMSO-d6) δ 10.55 (s, 1H), 9.71 (s, 1H), 8.16 (d, 1H, J=5.5 Hz), 7.63-7.55 (m, 2H), 7.29-7.23 (m, 2H), 6.68-6.63 (m, 1H), 2.02 (s, 3H), 1.48 (s, 9H); MS(ESI+): m/z 362.22 (M+H)+.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:15])[CH3:14].[Cl:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>>[Cl:16][CH2:17][CH2:18][NH:19][C:20]([N:15]([CH2:13][CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:21]
Reactant: CCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Product: CCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 88 %

Procedure:
3.6 g of D-glucose, 1.1 g of ethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 1-(1). 5.5 g of 1-(2-chloroethyl)-3-ethyl-3-D-glucopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13]C)[C:10]([CH3:12])([CH3:11])O2)=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[C:10]([CH3:11])([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: COC1(c2ccc(F)cc2)OC1(C)C
Product: CN1CCN(C(C)(C)C(=O)c2ccc(F)cc2)CC1
Temperature: 125 °C

Procedure:
29.43 g (0.15 mol) of 2-(4-fluorophenyl)-3,3-dimethyl-2-methoxyoxirane and 60.1 g (0.60 mol) of 1-methylpiperazine are brought together, and the mixture is heated to about 125° C. After 8 hours it is cooled down and the excess 1-methylpiperazine is distilled off. The residue is taken up in toluene, and the mixture is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and concentrated. The residue, 29.4 g of a cognac-coloured oil, is then further reacted.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16][CH2:15]1>C1(C)C=CC=CC=1>[C:3]([CH:5]=[C:20]1[CH2:21][CH2:22][C:17]2([O:24][CH2:14][CH2:15][O:16]2)[CH2:18][CH2:19]1)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC=C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (50% in mineral oil, 1.15 g, washed with hexane) in toluene (50 ml) is added a solution of diethyl cyanomethylphosphonate (4.25 g) in toluene (50 ml) dropwise under nitrogen and the mixture is stirred 30 minutes longer. A solution of 1,4-cyclohexanedione monoethylene ketal (3.12 g) in toluene (50 ml) is added dropwise under nitrogen at room temperature. After 10 minutes, ice water is added under vigorous stirring. The aqueous layer is collected and extracted several times with ether. The combined toluene-ether extracts are washed with water, then brine, dried over sodium sulphate and concentrated to dryness at reduced pressure. The residual oil is chromatographed through a 25×140 mm column of silica gel, using methylene chloride as solvent to afford an oil which gradually crystallizes to give 8-cyanomethylene-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH:19]=2)[O:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH:19]=2)[O:14]1)=[O:11]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CO)O3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](C=O)O3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 33 mg (0.425 mmol) dimethyl sulfoxide in 2 mL of methylene chloride at −78° C., was added 0.14 mL (0.272 mmol) 2M oxalyl chloride. After the solution had stirred at this temperature for 10 minutes, a solution of 50 mg (0.17 mmol) methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 16) in 2 mL of methylene chloride was added dropwise and the resulting mixture was stirred at −78° C. for an additional 1.6 hours. At this time, 0.14 mL (1.02 mmol) triethylamine was added to the mixture slowly, and then it was allowed to warm to room temperature over 15 minutes. The solution of desired product was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCCC5)sc34)ccc12

Procedure:
This material was prepared from the reaction of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone 28a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) □ 8.47 (1H, d, J=5.3 Hz), 7.82 (1H, s), 7.74 (1H, d, J=8.4 Hz), 7.14 (1H, d, J=1.7 Hz), 7.02 (1H, dd, J=1.7, 8.4 Hz), 6.55 (1H, d, J=5.3 Hz) 5.91 (1H, bs), 3.84 (2H, m), 3.70 (2H, m), 3.65 (3H, s), 3.05 (3H, d, J=4.5 Hz), 2.72 (3H, s), 2.02 (4H, m). LCMS (ESI+) [M+H]/z Calc'd 449. found 449.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:43][C:44]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:58]=[C:59](B(O)O)[CH:60]=[CH:61][CH:62]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])[CH3:45].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16]([C:15]3[CH:14]=[C:13]([CH2:12][N:10]([CH2:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:59]5[CH:60]=[CH:61][CH:62]=[C:57]([CH2:56][N:53]6[CH2:54][CH2:55][N:50]([C:48]([O:47][C:44]([CH3:46])([CH3:45])[CH3:43])=[O:49])[CH2:51][CH2:52]6)[CH:58]=5)[CH:3]=4)[CH3:11])[CH:42]=[CH:41][CH:40]=3)=[O:17])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(Br)c2)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 150 °C
Yield: 82 %

Procedure:
To a solution of 3-{[[(3-bromo-4-fluorophenyl)methyl](methyl)amino]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (0.37 g, 0.58 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (0.279 g, 0.87 mmol), Pd(PPh3)4 (33.6 mg, 0.029 mmol), and K2CO3 (0.32 g, 2.32 mmol). The mixture was heated with a microwave at 150° C. for 15 min. The organic layer was separated and concentrated. The residue was redissolved in EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 0.396 g (82%). LC-MS m/z 833 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=O)=[N:8][NH:9]2)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:21]=[CH:20][C:18]=1[NH2:19].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([B:24]4[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28]4)=[CH:23][C:17]=3[O:16][CH3:15])=[O:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To 6-methoxy-1H-indazole-3-carboxylic acid (64 mg, 0.333 mmol) in dichloromethane (10 ml) was added 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (166 mg, 0.666 mmol), O-(7-azabenzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.500 mmol) and N,N-diisopropylethylamine (0.174 ml, 0.999 mmol). The reaction mixture was stirred overnight at room temperature. Then the reaction mixture was concentrated in vacuo and the residue was purified by column chromatograpy (silica gel; dichloromethane/methanol 99/1) and thereafter by column chromatograpy (silica gel; heptane/ethyl acetate 2/1) to give 6-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-carboxamide (54 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:20].[OH-].[Na+]>O.Cl>[ClH:20].[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][NH2:13]
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccccc1OC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccccc1OC(F)(F)F
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of o-trifluoromethoxyaniline (1.77 g, 10 mmol) in cold, concentrated HCl (11.6 mL) was diazotized at -5° C. (internal temperature) with a solution of NaNO2 (0.69 g, 10 mmol) in water (11 mL). After 15-20 minutes the mixture was treated portionwise with a cold (0° C.) solution of tin (II)chloride dihydrate (4.5 g, 20 mmol) in concentrated HCl (4 mL). Stirring was continued for another 3 hours with the ice bath warming to room temperature after one hour. The suspension was recooled, basified with 50% NaOH (to pH 14) and extracted with ether. The extracts were washed with 1N NaOH, water and brine, dried (MgSO4) and acidified with an excess of ethereal HCl. Removal of the solvent in vacuo yielded the title compound as an off-white solid (2 g, 88%). It was used without further purification.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: O=C(Nc1ccncc1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-aminopyridine (Aldrich), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].Cl.CN.[CH2:24]([N:26](CC)CC)C.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[S:17]([NH:26][CH3:24])(=[O:19])=[O:18]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1OCC(F)(F)F
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])c(OCC(F)(F)F)cc1F
Temperature: -45 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A mixture of 2-fluoro-5-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonyl chloride (15 g, crude) in THF (150 mL) at −45° C. was treated with methylamine hydrochloride (5.96 g, 89 mmol) and then treated dropwise with triethylamine (12.4 mL, 89 mmol). After stirring for 1 hour at −45° C., the mixture was adjusted to pH 3 by the addition of aqueous 3M HCl, warmed to room temperature, diluted with water, and extracted with EtOAc. The organic extract was dried (Na2SO4), concentrated, and subjected to flash chromatography (9-17% EtOAc-petroleum ether) to give 2-fluoro-N-methyl-5-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (10 g, 72% for two steps) as a yellow solid. MS (m/z) 333.0 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:13])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O>[CH2:15]([C:6]1[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCl
Reactant: Cc1cc(C)cc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCCCCCCCc1c(C)cc(C)cc1C
Yield: 34.7 %

Procedure:
A 750 ml flask is charged with 6.7 g (50 mmol) of anhydrous aluminium chloride and 120.2 g (1 mol) of mesitylene. 148.7 g (1 mol) of 1-chloroctane are added dropwise to this mixture over 2 h at room temperature. HCl gas slowly evolves. The dark orange emulsion is stirred for c. 30 h at room temperature and then poured into water and extracted with toluene. The organic phase is isolated and concentrated on a rotary evaporator. The resultant oil is fractionated under vacuum to give, at 88°-92° C. and 1.8 mbar, 80.6 g of the title product as a colourless liquid. Gas chromatography (GC) and 1H-NMR spectrum analysis show that mono-n-octylmesitylene is obtained in 90% purity. The distillation residue contains mainly dioctylmesitylene.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.N([O-])=[O:23].[Na+]>C(O)(=O)C.O>[C@@H:12]1([N:8]2[C:6]3[NH:7][C:2](=[O:23])[NH:3][C:4](=[O:21])[C:5]=3[S:10][C:9]2=[O:11])[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14]
Reactant: O=N[O-]
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Reaction time: 0.5 h

Procedure:
To a suspension of 7 (0.76 g, 2.4 mmol) in glacial acetic acid (150 mL) was added dropwise a solution of sodium nitrite (1.5 g, 21.7 mmol) in water (15 mL) with stirring. After 30 min the suspension became clear and stirring was continued at room temperature overnight. The white solid which had separated was filtered, washed with cold water and dried. Recrystallization from hot water gave fine colorless crystals of 8: yield 0.3 g, 40%: mp 250° C. dec.: UV λmax (pH 1) 293 nm (ε5500): UV λmax (pH 7) 212 nm (ε14200), 301 (6100): UV λmax (pH 11) 204 nm (ε21900), 301 (5600). Anal. Calcd. for C10H11N3O7S: C, 37.86: H, 3.49: N, 13.24: S, 10.10. Found: C, 37.81: H, 3.42: N, 13.01: S, 10.01.