Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC([C@H]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([C@H:17]([O:19][C:20]3[C:21]4[N:22]([N:45]=[CH:46][CH:47]=4)[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[CH:28][CH:27]=4)[CH:25]=3)[CH3:18])[CH2:12]2)C)=CC=1>C(O)(C(F)(F)F)=O>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:24]3[CH:25]=[C:20]([O:19][C@@H:17]([C@H:13]4[CH2:12][NH:11][C:15](=[O:16])[CH2:14]4)[CH3:18])[C:21]4[N:22]([N:45]=[CH:46][CH:47]=4)[CH:23]=3)=[CH:31][CH:30]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4nccc34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Temperature: 60 °C

Procedure:
Tert-butyl 4-(4-(4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate 6.15 (50 mg, 0.078 mmol) was dissolved in TFA (2.0 mL) and heated at 60° C. for 18 h. The reaction was concentrated to dryness (solvent exchange was performed with acetonitrile and toluene) and the residue was passed through a polymer-supported bicarbonate column to provide (R)-4-((R)-1-((6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.16, as the free base, and was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19](N)=[O:20])=[N:16][C:15]([O:22][CH3:23])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)(=O)C>O1CCCC1.CO.[H-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Zr+4]>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[CH2:19][OH:20])=[N:16][C:15]([O:22][CH3:23])=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2ncc(OCc3ccccc3)c(C(N)=O)c2n1
Agent: [Zr+4]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCc3ccccc3)c(CO)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A solution of 3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-carboxylic acid amide (640 mg, 2.07 mmol, 1.0 eq) in tetrahydrofuran (50 mL) is added at room temperature to a flask charged with Schwartz's reagent (800 mg, 3.1 mmol, 1.5 eq) and the resulting mixture is stirred at room temperature for 10 minutes. Solvent is removed to give a crude that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:1, v/v) to afford a mixture of aldehyde and alcohol. This mixture is dissolved in methanol (20 mL) and sodium borohydride (39 mg, 1.03 mmol, 0.5 eq) is added at room temperature. After 5 minutes stirring at room temperature, solvent is removed to give a crude that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 4:1, v/v) to afford (3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-yl)-methanol as a white solid (390 mg, 64% yield).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:18]([O-])([O-])[O:19][CH2:20][CH3:21].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][O:19][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Br
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Temperature: 150 °C
Yield: 79.7 %

Procedure:
A mixture of ethyl (2-bromo-4,5-difluorobenzoyl)acetate (52.0 g), ethyl orthoformate (36.6 g) and acetic anhydride (41.6 g) is heated at 150° C. for 2 hours. After the reaction, the reaction mixture is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane: n-hexane =2:1) to give ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-ethoxyacrylate (49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([CH:25]=O)[CH:22]=[CH:21][N:20]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)[CH:7]=3)[N:1]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cc1cc(C=O)ccn1
Reactant: NC(=O)c1cc(CN2CCOCC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CN4CCOCC4)cc3c(=O)[nH]2)ccn1
Temperature: 115 °C

Procedure:
To a solution of 2-amino-5-morpholin-4-ylmethyl-benzamide (0.58 g, 2.4 mmol) and 2-methyl-pyridine-4-carbaldehyde (0.3 g, 2.4 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (58.5 wt %, 0.48 g, 2.7 mmol) and p-TSA (0.23 g, 1.2 mmol) and the reaction mixture was heated at 115° C. for 16 hours, and the solvent was removed under reduced pressure. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with 4% methanolic ammonia in dichloromethane) to give the title compound as a white solid. Yield: 0.18 g (22%). MP 267-268° C. 1H NMR (400 MHz, DMSO-d6): δ 11.74 (br s, 1H), 8.77 (d, J=5.4 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.94-7.83 (m, 3H), 3.75 (t, J=4.2 Hz, 4H), 3.74 (s, 2H), 2.77 (s, 6H), 2.53-2.46 (m, 4H). MS (ES+) m/z: 337.41 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:38]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[O:38])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1CCN(C(=O)c2ccccc2N)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCN(C)CC3)n2)c(OC)c1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available (2-aminophenyl)-(4-methylpiperazin-1-yl)-methanone. MS (ES+): m/z 637.40 (100) [MH+]; HPLC: tR=0.69 min (UPLC, purity).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH:2]=[CH2:3].[O:12]=[CH:13]C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[OH:11])[CH:13]=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1O
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCOc1cc(C=O)ccc1O
Reaction time: 8 h

Procedure:
149 g (1 mol) of o-allyloxyphenol and 180 g (1.22 mols) if chloral are fused by gentle warming, 100 g of finely powdered sodium carbonate are added at 25° C and the mixture is subsequently stirred for 8 hours. The resulting viscous mass is stored for 5 days at room temperature and then introduced into 500 ml of water. The whole is thoroughly stirred, the water is decanted and washing is repeated three more times, with 250 ml of water at a time. The viscous oil which remains is crude 2-allyloxy-4-(1-hydroxy-2-trichloro-ethyl)-phenol. This is introduced into a solution of 250 g of potassium hydroxide in 500 ml of methanol at 30° C over the course of 2-3 hours and the reaction mixture is left to stand for 3 hours. The alkali metal salts which have precipitated are filtered off and the filtrate is evaporated under reduced pressure. The oily residue is converted into a slurry with ice water, acidified with hydrochloric acid and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulphate and then filtered through a 3 cm thick layer of Merck silica gel (0.063-0.20). After washing with chloroform, evaporation of the filtrate under reduced pressure and crystallisation of the residue from hexane yields 3-allyloxy-4-hydroxy-benzaldehyde of melting point 66°-67° C.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:24]([OH:26])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:6])[CH3:3].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:43][N:44]([N:51]=O)C(N[N+]([O-])=O)=N>O1CCCC1>[N+:44](=[CH:43][C:24](=[O:26])[C@@H:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:27])[CH3:3])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)=[N-:51]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)C=[N+]=[N-]
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-[(1,1-dimethylethoxy)carbonyl]--O-benzyl-L-tyrosine in dry tetrahydrofuran (90 ml) cooled at -20° C. to -25° C. was added isobutyl chloroformate (8.7 ml, 67.3 mmol) followed by 4-methylmorpholine (6.8 ml, 67.3 mmol) and the mixture was stirred for 20 minutes. The precipitate was filtered and washed with dry tetrahydrofuran. The filtrate was cooled to -5° C. and poured into a diazomethane in ether solution (prepared from 1-methyl-3-nitro-1-nitrosoguanidine (29.7 g, 202 mmol) as described in Example 1 (d) at 0° C. The resulting yellow solution was kept at 0° C. for 2.0 hours, then at room temperature overnight. Nitrogen was then bubbled through the solution for 30 minutes, the solution diluted with ethyl ether (500 ml) and then washed with water, saturated sodium bicarbonate, and brine, and dried over magnesium sulfate. Concentration in vacuo afforded a yellow residue which was triturated with hexane (500 ml) to give 24.5 g of (S)-[3-diazo-2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]propyl]carbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([O:23][Si](C)(C)C)C#N)=[C:16]([F:28])[CH:15]=1.[C:29]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)(=[O:31])[CH3:30]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:35]2([OH:38])[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]2)=[O:23])=[C:16]([F:28])[CH:15]=1
Reactant: C[Si](C)(C)OC(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)(C(=O)c2ccc(Cl)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of diisopropylamine (4.42 mL, 31.59 mmol) in THF (20 mL) at 0° C. under Ar, was added n-BuLi (12.63 mL, 31.59 mmol, 2.5 M solution in hexane). The mixture was stirred at 0° C. for 30 min. After cooling to −78° C., (4-chloro-2-fluoro-phenyl)-trimethylsilanyloxyacetonitrile (8.12 g, 31.59 mmol) was added. After stirring at −78° C. for 1.5 h, 1-acetyl-piperidin-4-one (4.45 g, 31.59 mmol) was added. The final mixture was stirred at −20° C. for overnight. After concentration, EtOAc (100 mL) was added. The organic phase was washed with Sat. NH4OAc solution, Sat. NaHCO3 solution and concentrated. The residue was dissolved in MeOH (30 mL). 1N HCl solution (20 mL) was added. The mixture was stirred at RT for 2 h. After concentrating the mixture, EtOAc (50 mL) was added. The organic layer was basified with Sat. NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product (4 g, 42% yield) as a white solid. MS: (ESI), M/Z, 300 (M+1). Retention time: 0.87 min (FA-standard).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccccc1NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6 g. portion of 3-(2-fluorophenylaminomethyl)pyridine was dissolved in 50 ml. of acetone, and 5 g. of potassium carbonate and 5 g. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature overnight, and then under reflux for 6 hours. The mixture was cooled and filtered, and the filtrate was concentrated under vacuum to obtain 7.4 g. of an oil, which was chromatographed on silica gel, eluting with 1:4 acetone:toluene. Combination of the product-containing fractions and evaporation gave 9.7 g. of the desired product, m.p. 120°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+].O>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:5]1[CH:6]=[N:7][C:2]([O:24][CH3:23])=[CH:3][CH:4]=1
Reactant: C[O-]
Reactant: COc1cc2nccc(Oc3ccc(Cl)nc3)c2cc1OC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cn1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
4-(6-Chloro-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 206) (145 mg) and sodium methoxide (87 mg) were suspended in toluene (1.2 ml), and the suspension was heated under reflux for 20 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (88 mg, yield 61%).
Reaction SMILES: [F-].[NH4+].[Si]([O:10][C@H:11]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=1)[CH2:12][NH:13][C@H:14]([CH3:33])[CH2:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([NH:25][CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:24])[CH:19]=[CH:20][CH:21]=1)(C(C)(C)C)(C)C>CO.O>[CH:26]1([NH:25][C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][C@H:14]([NH:13][CH2:12][C@H:11]([OH:10])[C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=3)[CH3:33])[CH:17]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C[C@H](Cc1cccc(CC(=O)NC2CCCCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C[C@H](Cc1cccc(CC(=O)NC2CCCCCC2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 40 °C
Yield: 73.6 %

Procedure:
Ammonium fluoride (98 mg, 2.64 mmol) was added in one portion to a stirred solution of 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cycloheptylacetamide (Preparation 1) (150 mg, 0.26 mmol) in methanol (3 ml) and water (1.5 ml) at room temperature. The reaction was heated at 40° C. for 18 hours and then allowed to cool to room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (30 ml) and water (20 ml), the organic layer was separated, washed with brine (10 ml), dried (magnesium sulfate) and the solvent removed in vacuo to yield a clear oil. This was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol: ammonia (90:10:1 by volume) to furnish the title compound as a white foam (87 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CN2CCCCC2)c1
Reaction time: 20 h
Yield: 94.5 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)phenol (11.2 g) sodium hydride (1.5 g) and ethyl 4-bromobutyrate (11.7 g) in dimethylformamide (60 ml) was stirred at 25° during 20 h. The mixture was poured onto ice (300 g) and extracted with ethyl acetate (3×100 ml). The combined extracts were distilled to give the title compound as a colourless oil (16.9 g) b.p. 250°, 0.1 mm; tlc System B, Rf 0.9.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][CH2:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:11])[C:4]=2[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>[Cu]I.CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[CH:28][N:29]([C:2]3[CH:17]=[CH:16][C:5]4[O:6][CH2:7][CH2:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:11])[C:4]=4[CH:3]=3)[CH:30]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)C1=C(C)c2cc(Br)ccc2OCC1
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Agent: [Cu]I
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)c2cc(-n3cnc(-c4ccc(OC)cc4)c3)ccc2OCC1
Temperature: 120 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
To an oven dried microwave vial was added methyl 7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepine-4-carboxylate from step H5 (200 mg, 0.673 mmol), 4-(4-methoxyphenyl)-1H-imidazole (141 mg, 0.808 mmol), potassium carbonate (186 mg, 1.35 mmol) and copper(I) iodide (72.9 mg, 0.383 mmol). The vial was capped with a septum and the system was degassed and flushed with nitrogen (3×). Then 2,2,6,6-tetramethylheptane-3,5-dione (0.194 mL, 0.944 mmol) and DMF (5 mL) were added and the reaction mixture was degassed and flushed with nitrogen (3×). The vial was sealed and place in a pre-heated oil bath at 120° C. The reaction mixture was stirred at 120° C. for 20 h. The reaction was poured into water to afford a blue mixture that was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (30-100% EtOAc/hexanes) to afford methyl 7-(4-(4-methoxyphenyl)-1H-imidazol-1-yl)-5-methyl-2,3-dihydrobenzo[b]oxepine-4-carboxylate (180 mg, 0.461 mmol, 69% yield). LCMS (M+H)+=391.1. 1H NMR (500 MHz, chloroform-d) δ 7.88 (br. s., 1H), 7.77 (d, J=7.2 Hz, 2H), 7.39-7.33 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 6.94 (d, J=7.5 Hz, 2H), 4.59 (t, J=6.0 Hz, 2H), 3.87-3.82 (m, 6H), 2.57 (t, J=5.9 Hz, 2H), 2.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]2[O:12][C:11]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[N:10][CH:9]=2)=[C:4]([N+:25]([O-])=O)[CH:3]=1>[Zn]>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]2[O:12][C:11]([Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:14]([CH3:15])[CH3:16])=[N:10][CH:9]=2)=[C:4]([NH2:25])[CH:3]=1
Reactant: CC(C)[Si](c1ncc(COc2ccc(Cl)cc2[N+](=O)[O-])o1)(C(C)C)C(C)C
Agent: [Zn]
Product: CC(C)[Si](c1ncc(COc2ccc(Cl)cc2N)o1)(C(C)C)C(C)C

Procedure:
5-(4-Chloro-2-nitro-phenoxymethyl)-2-triisopropylsilanyl-oxazole was reduced utilizing zinc dust as described in Preparation 20, Step B, to give 100 mg of 5-chloro-2-(2-triisopropylsilanyl-oxazol-5-ylmethoxy)-phenylamine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][C:4]=1[F:10])[CH3:2].ClC1C=C[N:15]=[C:14](C#N)C=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]#[N:15])[C:4]=1[F:10])[CH3:2]
Reactant: CCc1cc[n+]([O-])cc1F
Reactant: N#Cc1cc(Cl)ccn1
Product: CCc1ccnc(C#N)c1F

Procedure:
The title compound was prepared from 4-ethyl-3-fluoropyridine-N-oxide according to the procedure for preparing 4-chloro-2-pyridinecarbonitrile described in Example 33.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 82.1 %

Procedure:
Following general procedure II, (S)-tert-butyl (1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (83 mg, 0.31 mmol) to afford the product (102 mg) which was carried forward without any purification: ESI MS m/z 621 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:11])[CH2:8][C:9]#[N:10].[C:12]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](=O)[CH2:26][Cl:27])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:27][C:26]1[CH:25]=[CH:20][CH:21]=[CH:22][C:23]=1[C:24]1[C:8]([C:9]#[N:10])=[C:7]([NH2:11])[N:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: O=C(CCl)c1ccccc1Nc1ccccc1
Reactant: N#CCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1c(-c2ccccc2Cl)cn(-c2ccccc2)c1N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
4.0 g of potassium tertiary butoxide are dissolved in 80 ml of ethanol and subsequently first 3.0 g of malononitrile and then 9 g of 2'-phenylamino-2-chloroacetophenone are added at RT and the mixture is stirred at 65° C. for 2 h. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted once more with methylene chloride. The combined organic phases are dried over MgSO4 and concentrated. The product is chromatographed on silica gel using methylene chloride and the product-containing fractions are concentrated, 4-(2-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole being obtained as a reddish, viscous oil which is directly further processed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[SH:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>CN(C=O)C.O>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([S:10][CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[CH:5]=1
Reactant: COc1ccc(Br)cc1S
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1SCc1ccccc1C#N
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
As depicted in Scheme 7 above, to a solution of 104 mg (0.470 mmol) of 2-methoxy-5-bromo-thiophenol in 5 mL of DMF was added 162 mg (1.18 mmol) of anhydrous to a solution of 104 mg (0.470 mol) of 2-methoxy-5-bromo-thiophenol in 5 mL of DMF was added 162 mg (1.18 mol) of anhydrous K2CO3. The solution was stirred for 15 minutes at 22° C. and 103 mg (0.520 mmol) of 2-bromomethyl-benzonitrile was added. The reaction was capped and heated to 40° C. for 12 hours. The mixture was subsequently diluted with 5 mL of water and extracted with ethyl acetate (2×10 mL). The organic extracts were washed with water (3×10 mL), brine (2×10 mL), and dried (Na2SO4). The solvent was evaporated and the product was purified on silica gel (eluting with 9:1 of hexane/ethyl acetate) to afford 102 mg of the product as a colorless oil.