Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B([O-])=O.[Na+].[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])=[CH:8][CH:7]=1.C(O)(=O)C>CO>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:12]([OH:18])[C:13]([CH3:16])([CH3:17])[CH:14]=[CH2:15])=[CH:24][CH:25]=1
Reactant: C=CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Agent: O=B[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Reaction time: 6 h
Yield: 79.5 %

Procedure:
3.8 g (0.1 mol) of sodium boranate were introduced in portions into a solution of 15.3 g (0.05 mol) of 5-(4-chlorophenoxy)-3,3-dimethyl-5-(imidazol-1-yl)-pent-1-en-4-one (obtained as described in Example 1) in 150 ml of methanol, the mixture being cooled externally. After 6 hours, the reaction mixture was adjusted to pH 6 with dilute acetic acid, and was concentrated by evaporation under reduced pressure. The residue was taken up in ethyl acetate, and the solution was washed once with dilute sodium bicarbonate solution and three times with water, dried over sodium sulphate and thereafter concentrated in vacuo. The oily residue was dissolved in a small amount of ether and petroleum ether was added to the solution. The resulting precipitate was separated off, washed with a small amount of petroleum ether and dried. 12.2 g (79.7% of theory) of 5-(4-chlorophenoxy)-3,3-dimethyl-5-(imidazol-1-yl)-pent-1-en-4-ol of melting point 88° to 90° C. were obtained.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[CH3:58])[N:49]=[CH:50][C:43]=12)[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[C:43]2[CH:50]=[N:49][N:48]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[CH3:58])[C:44]=2[N:45]=[CH:46][N:47]=1)[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1C
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cccc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(C#N)cn3)ncnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
A solution of 2M Trimethyl aluminium in toluene (1.790 mL, 3.58 mmol) in toluene (15 mL) was added dropwise to a stirred suspension of 6-aminonicotinonitrile (0.426 g, 3.58 mmol) in toluene (15 mL) cooled to 0° C., over a period of 2 minutes under nitrogen and the resulting suspension stirred for 20 minutes at 0° C. A solution of (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AE2) (1.05 g, 1.63 mmol) in toluene (10 mL) was added dropwise over 2 minutes, the mixture allowed to warm to ambient temperature and then heated to 60° C. for 20hrs. Cooled to ˜5° C. and a 10% solution of Rochelle's salt (25 mL) added followed by ethyl acetate (30 mL) and stirred at ambient temperature for 30 minutes. The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated to a yellow gum. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (1.1 g, 92%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, s), 2.03 (3H, s), 3.71-3.78 (4H, m), 4.05-4.10 (1H, m), 4.14-4.19 (1H, m), 6.00-6.02 (1H, m), 7.34-7.45 (8H, m), 7.59-7.61 (4H, m), 7.67-7.69 (1H, m), 8.11-8.14 (1H, m), 8.20-8.23 (1H, m), 8.51 (1H, s), 8.84 (1H, s), 8.80-8.82 (1H, m), 11.55 (1H, s); m/z (ESI+) (M+H)+=732; HPLC tR=3.48 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1)[CH3:28].[BH4-].[Na+].CC(C)=O>C(O)C.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:40][C:37]([CH3:38])([CH3:39])[CH2:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:27][CH3:28])=[CH:31][CH:32]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CCOc1ccc(CC(C)(C)N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1
Temperature: 25 °C

Procedure:
2.14 g (6.0 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 1.0 g (5.2 mmol) of 2-(4-ethoxyphenyl)-1,1-dimethylethylamine are stirred in 40 mL ethanol for one hour at 50° C.-80° C. After cooling to ambient temperature, 0.23 g (6.0 mmol) of sodium borohydride are added and the mixture is stirred for a further hour. The reaction mixture is combined with 5 mL acetone, stirred for 30 minutes, acidified with glacial acetic acid, and evaporated down. The residue is combined with water and ethyl acetate and made alkaline. The organic phase is separated off, washed with water, dried with sodium sulfate, and freed from solvent in vacuo. The residue is dissolved again in ethyl acetate and water, combined with concentrated hydrochloric acid, and diluted with diethyl ether. The solid precipitated is suction filtered and washed with diethyl ether. White solid. Yield: 2.0 g (61%, hydrochloride); melting point: 214° C.-216° C.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4[N:17]([N:29]=[CH:30]N=4)[C:18]([C:21]4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:44]=[CH:45][C:46]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[C:47]([CH2:49][OH:50])[CH:48]=2)=[N:35][CH:34]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.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>[NH:17]1[CH:18]=[C:21]([C:33]2[N:38]3[N:39]=[CH:40][N:41]=[C:37]3[C:36]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[C:47]([CH2:49][OH:50])[CH:48]=3)=[N:35][CH:34]=2)[CH:30]=[N:29]1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: OCc1cc(Nc2ncc(Br)n3ncnc23)ccc1N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: OCc1cc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)ccc1N1CCOCC1

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using [5-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-2-morpholin-4-yl-phenyl]-methanol (85 mg, 0.21 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-1H-pyrazole (81 mg, 0.42 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) in 1.5M Na2CO3 (1.12 mL) and dioxane (2.0 mL). The reaction mixture is purified by silica gel column chromatography, eluting with 95:3 DCM:NH3 (7M in MeOH) followed by reverse phase preparative HPLC purification. The title compound is obtained as a pale brown solid (10 mg, 12%). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 2.87 (4H, m), 3.77 (4H, m), 4.63 (2H, d), 5.12 (1H, t), 7.11 (1H, d), 7.84 (1H, d), 8.12 (1H, s), 8.21 (1H, s), 8.39 (1H, s), 8.69 (1H, s), 8.77 (1H, s), 9.78 (1H, s), 13.29 (1H, br s). LCMS: Rt 2.45 min (96.3%), m/z (APCI) 393 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:25]([Mg]Br)[CH3:26]>O1CCCC1.C(OCC)C.[Cl-].[Na+].O>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH2:25][CH3:26]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCC(O)c1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 0.3 g (0.7 mmol) of material from Example 45 in 4 mL of tetrahydrofuran at ambient temperature was added 0.5 mL (1.5 mmol) of a 3.0M solution of ethylmagnesium bromide in ethyl ether. The mixture was stirred for 16 hours, diluted with 5 mL of half saturated brine and extracted four times with 5 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (15 g silica gel, 50% ethyl acetate/hexane) of the residue afforded 0.1 g (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: Nc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(Nc2ccc(Cl)nc2)c(C(=O)O)c1
Temperature: 130 °C
Yield: 46 %

Procedure:
A mixture of 6-chloropyridin-3-amine (11.67 mmol, 1.5 g) and 2-bromo-5-methylbenzoic acid (23.34 mmol, 5.02 g), Cu (1.17 mmol, 0.1 g), Cu2O (0.58 mmol, 0.1 g) and K2CO3 (23.34 mmol, 3.2 g) in 1,2-dimethoxyethane (15 ml) was heated at 130° C. for 16 hours, under argon atmosphere. Water was added and the mixture was filtered through celite. HCl 2N aqueous solution was added until pH 6 and the solid formed was filtered off. The crude was purified by chromatography eluting with DCM/MeOH mixtures affording 1.40 g (yield 46%).
Reaction SMILES: [I:1][C:2]1[C:7]([NH2:8])=[C:6]([I:9])[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12]S(OC)(=O)=O.C(OCC)(=O)C>O1CCCC1>[I:1][C:2]1[C:7]([NH:8][CH3:12])=[C:6]([I:9])[N:5]=[CH:4][N:3]=1
Reactant: COS(C)(=O)=O
Reactant: Nc1c(I)ncnc1I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1c(I)ncnc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,6-diiodopyrimidin-5-amine (1.0 g) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 138 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min. To the reaction system was added dropwise a solution of methyl methanesulfonate (0.256 mL) in tetrahydrofuran (4.0 mL). The mixture was stirred at room temperature for 3 hrs and ethyl acetate was added. The mixture was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give the title compound (600 mg) as pale-yellow crystals.
Reaction SMILES: ClC(OCC)=O.C([N:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:17]3([CH2:16][CH2:15][NH:14][CH2:19][CH2:18]3)[CH2:23][C:22]=2[CH:24]=1
Reactant: Fc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Yield: 46.9 %

Procedure:
Ethyl chloroformate (65.6 mg, 0.604 mmol) was added to a solution of 1′-benzyl-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidine] (150 mg, 0.504 mmol) in toluene (2 mL) and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, diluted by addition of toluene, washed successively with aqueous sodium hydrogencarbonate (NaHCO3) and water. The organic layer was dried over sodium sulphate (Na2SO4) filtered and concentrated in vacuo. The residue was dissolved in ethanol (3.5 mL), aqueous potassium hydroxide (KOH) (800 mg KOH in 0.8 mL water) was added and the reaction mixture was kept on stirring at reflux overnight, cooled to room temperature, extracted with ethyl acetate. The organic layer was well washed with water, dried over sodium sulphate (Na2SO4), filtered and concentrated. The residue was purified by HPLC (10% acetonitrile (CH3CN)-55% CH3CN in water containing 0.1% ammonium hydroxide, NH4OH) to give the titled compound (49 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:14]([CH3:17])[CH:15]=2)[C@H:10](N(CC2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)C#N)[CH2:9][C@@H:8]1[CH2:44][CH3:45])=[O:6])([CH3:3])[CH3:2].[N-]=[N+]=[N-].[Na+].Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:14]([CH3:17])[CH:15]=2)[CH2:10][CH2:9][CH:8]1[CH2:44][CH3:45])=[O:6])([CH3:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(NCc3ccccc3)c(C)cc2N1C(=O)OC(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC1CCc2nc(NCc3ccccc3)c(C)cc2N1C(=O)OC(C)C
Temperature: 110 °C
Reaction time: 15 h
Yield: 31.3 %

Procedure:
Heat at 110° C. a mixture of (+/−)-cis-6-benzylamino-4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-7-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (110 mg, 0.174 mmol), sodium azide (16 mg, 0.244 mmol) and triethyl amine hydrochloride (33 mg, 0.244 mmol) in dry toluene under a nitrogen atmosphere for 15 h. Then add more sodium azide (10 mg) and triethyl amine hydrochloride (25 mg) and heat the mixture for 20 h. Cool to room temperature, dilute with ethyl acetate, and wash with 1 N HCl. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate. Dissolve the residue in dry dichloromethane (1 mL), add triphenylphosphine (38 mg, 0.146 mmol), methanol (22 mg, 0.66 mmol) followed by diisopropylazodicarboxylate (0.046 mL, 0.104 mmol) and stir the mixture for 15 h at room temperature. Remove the solvent in vacuo and purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford (+/−)-trans-4-[(3,5-bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-benzylamino-7-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester [15 mg, 16%, MS (ES+): 691 (M+H)] and (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-benzylamino-7-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester [20 mg, 22%, MS (ES+): 691 (M+H)].
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:30][C:31](=O)[CH3:32]>>[CH3:32][C:31]1[N:27]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:28][CH:30]=1
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(=O)CCl
Product: Cc1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (about 0.182 mmol) of the compound from Example 115A and 25 mg (0.273 mmol) of 1-chloropropan-2-one were reacted according to the General Method 3. Yield: 40 mg (44% of theory).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O.C(OCC)(=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:4]1[C:3](=[O:11])[CH2:2][O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2
Reactant: ClCCCBr
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of 2H-1,4-benzoxazin-3(4H)-one (1.0 g, 6.7 mmol) and potassium carbonate (1.4 g, 10.05 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (1.99 mL, 20.1 mmol, d=1.6). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to the title compound (1.46 g, 97%); 1H NMR (DMSO-d6): δ 1.99-2.03 (m, 2H), 3.71 (t, 2H, J=6.4 Hz), 4.00-4.04 (m, 2H), 4.63 (s, 2H), 7.00-7.01 (m, 2H), 7.03-7.09 (m, 1H), 7.22 (d, 1H, J=7.6 Hz); MS for C11H12ClNO2 m/z 225.96 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>CN(C)C=O.C(OCC)(=O)C>[I:20][C:21]1[CH:22]=[C:23]([CH2:24][N:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cccc(I)c1
Reactant: CCS(=O)(=O)NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)Cc1cccc(I)c1

Procedure:
A solution of N-(ethylsulfonyl)pyrid-3-ylmethylamine (1.1 g, 5.5 mmol), cesium carbonate (1.79 g, 5.5 mmol), and 3-iodobenzyl bromide (1.64 g, 5.5 mmol) was stirred in N,N-dimethylformamide (25 ml) for 5 h at room temperature. The mixture was diluted with ethyl acetate (100 ml) and washed four times with water (50 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated in vacuo to a crude residue. The residue was purified by radial chromatography on a 4 micron silica plate eluting with 3% methanol/dichloromethane to afford the title compound. 1H NMR: 8.6 (d,1H,J=4 Hz), 8.41 (s,1H), 7.75 (m,1H), 7.65 (m,1H), 7.60 (s,1H), 7.25-7.40 (m,2H), 7.08 (m,1H), 4.43 (s,2H), 4.33 (s,2H), 3.08 (q,2H,J=8 Hz), 1.43 (t,3H,J=8 Hz). MS calcd. 416.3; MS (M+1) 417.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=2[CH2:29][CH2:28]1>>[Cl:22][C:5]1[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])=[N:7][C:2]([NH:38][C:35]2[CH:36]=[CH:37][C:30]3[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH2:33][CH2:32][C:31]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Fc1cccc(OC2CCOC2)c1Oc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Oc4c(F)cccc4OC4CCOC4)n3)cc2CC1

Procedure:
Title compound was prepared from 2,5-Dichloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenoxy]-pyrimidine and 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 1d. Title compound was isolated as a white solid. HPLC purity=99%, LCMS=531.32 (M+H), 1HNMR (CDCl3, 400 MHz) δ 9.00 (bs, 1H), 8.24 (s, 1H), 7.28-7.16 (m, 3H), 7.16-7.14 (m, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.29 (bs, 1H), 4.97 (s, 1H), 3.86-3.78 (m, 8H), 3.38-3.32 (m, 7H), 2.85-2.81 (m, 3H), 2.60-2.55 (m, 1H), 2.09-1.95 (m, 2H).
Reaction SMILES: [Br-].[CH2:2]([N:4]([C:7]1[O:8][C:9]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20]C=CC=3[P+](C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)C=O)[CH3:3].[CH2:36]([N:43]1[CH:47]=[CH:46][N:45]=C1C=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH2:36]([N:43]1[CH:47]=[CH:46][N:45]=[C:20]1[CH:21]=[CH:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([NH:4][CH2:2][CH3:3])[O:8][C:9]=2[CH:15]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCN(C=O)c1nc2ccc(-c3ccccc3[P+](C)(c3ccccc3)c3ccccc3)cc2o1
Reactant: O=Cc1nccn1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1nc2ccc(C=Cc3nccn3Cc3ccccc3)cc2o1
Yield: 63.3 %

Procedure:
A mixture of [2-(N-ethylformamido)benzoxazol-6-yl]-methyltriphenylphosphonium bromide (0.5 g), 1-benzyl-2-imidazolecarbaldehyde (0.2 g) and potassium tert-butoxide (0.1 g) in tetrahydrofuran (5.0 ml) was refluxed for 50 minutes. Evaporation of a solvent gave a residue, which was purified by a column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 6-[2-(1-benzylimidazol-2-yl)vinyl]-2-ethylaminobenzoxazole (0.2 g).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]2[C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=3[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(S(N)(=O)=O)cc3)c3c(OC)nccc32)cc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(Cn2nc(-c3ccc(S(N)(=O)=O)cc3)c3c(=O)[nH]ccc32)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 4-(4-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (42.0 mg) in acetonitrile (3 mL) were added sodium iodide (37.1 mg) and chloro(trimethyl)silane (0.126 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (33.1 mg).