Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].COC(C)=C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.[H-].[Na+]>C1COCC1.CN(C=O)C>[OH:4][CH2:3][CH2:2][N:16]1[C:17]2[C:13](=[CH:12][C:11]([Br:10])=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OCCBr
Agent: C=C(C)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCCn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
Under a N2 atmosphere, 2-bromoethanol (17.6 g, 141 mmol) and 2-methoxypropene (10.1 g, 141 mmol) were stirred in 71 mL of THF at 0° C. for 30 minutes The resulting solution was added to a stirring mixture of 5-bromoindole (22.83 g, 116 mmol) and 60% NaH (4.62 g, 193 mmol) in 40 mL of DMF and 60 mL of THF. The solution was stirred at ambient temperature for 4 hours. The reaction mixture was worked up by quenching the excess of NaH with water and removing the aqueous layer. The organic layer was vigorously stirred with 200 mL of 2% aqueous phosphoric acid for 5 hours when the layers were separated. The organic layer was washed with water (2×200 mL) and the solvent removed. The residue was purified by column chromatography (30:70 EtOAc-Hex) to give 17 g of 1-(2-hydroxylethyl)-5-bromoindole.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]([F:15])([F:14])[F:13])=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:18])=O.O>C1(C)C=CC=CC=1>[Cl:18][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]([F:15])([F:14])[F:13])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccc1OC(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(CCl)ccc1OC(F)(F)F
Temperature: 75 °C
Yield: 73.7 %

Procedure:
5-(Hydroxymethyl)-2-(trifluoromethoxy)benzonitrile (0.150 g, 0.691 mmol) was taken up in toluene (2 mL) and thionyl chloride (0.303 mL, 4.14 mmol) was added. The mixture was heated at 75° C. for 15 min. Water was added and the mixture was extracted with hexanes (2×75 mL). The organics were treated with aqueous NaHCO3. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (120 mg). LCMS m/z=236.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 1.98 (s, 1H), 4.52 (s, 2H), 7.32-7.34 (m, 1H), 7.59-7.62 (m, 1H), 7.68 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F-].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B(O)O.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O.CC(O)C>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[CH:9][CH:8]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: N#Cc1cc(F)ccc1Br
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)ccc1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A suspension of 2-bromo-5-fluorobenzonitrile (10.0 g, 50 mmol), potassium fluoride (9.59 g, 165 mmol) and 2,6-difluorophenylboronic acid (9.87 g, 62.5 mmol) in tetrahydrofuran (120 ml) and water (15 ml) was degassed with nitrogen for 30 min. Tris(dibenzylidineacetone)-dipalladium(0) (916 mg, 1.0 mmol) and tri-tert-butylphosphine (10% w/w solution in hexane, 0.5 ml) were added and the mixture stirred at ambient temperature for 18 h. The black solution was washed with 1N sodium hydroxide solution (2×100 ml), and the aqueous phase was re-extracted with diethyl ether (100 ml). The combined organic layer was washed with brine (50 ml), filtered through a glass microfibre filter paper then evaporated to give an orange solid. The solid was suspended in 2-propanol (120 ml) and heated to 70° C. to aid dissolution. The solution was left to cool to ambient temperature then water (120 ml) added dropwise over 1 h. The solid was filtered and washed with 2-propanol/water (1:1, 30 ml) then dried under vacuum to give 4,2′,6′-trifluorobiphenyl-2-carbonitrile (9.92 g, 85%) as a grey solid: δH (360 MHz, CDCl3) 7.06 (2H, t, J 8), 7.38-7.52 (4H, m).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:30])=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[Cl:30][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:3][NH:4]3)=[CH:9][CH:8]=2)=[O:12])=[CH:18][C:17]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3c(-c4ccccc4)c[nH]c3c2)ccc1Cl
Temperature: 130 °C

Procedure:
To a mixture of 0.1 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide, 0.039 g of phenylboronic acid and 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethane complex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassium phosphate in water (1.2 mL). The solution is heated to 130° C. for 5 minutes (microwave irradiation). The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried (magnesium sulfate) and concentrated to 0.094 g of crude product. Purification via flash chromatography on silica gel (98:2 methylene chloride/methanol) afforded 2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide as a tan powder. MS (m/z): 409 (M−1); Rf 0.22 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1

Procedure:
Prepared according to Procedure S using 3-bromo-5-nitrobenzoic acid (5.0 g, 20.32 mmol), potassium carbonate (5.62 g, 40.6 mmol), DMF (55 mL), and methyl iodide (2.54 mL, 40.6 mmol) to afford methyl 3-bromo-5-nitrobenzoate as an orange amorphous solid. Mass Spectrum (ESI) m/e=261.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 83.6 %

Procedure:
At 100° C., 167.0 g of 4-hydroxy-3-nitrobenzaldehyde, 311.0 g of potassium carbonate, and 211.0 g of benzyl chloride are agitated in 2 l of dimethylformamide for 16 hours. The resultant reaction mixture is poured into 10 l of water, the thus-separated solid product is filtered off and recrystallized from ethanol, yielding 215.0 g of 4-benzyloxy-3-nitrobenzaldehyde, mp 100°-102° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>O.C(OCC)(=O)C>[OH:13][C:14]1([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:3][C:4](=[O:7])[O:5][N:48]=5)=[CH:39][CH:40]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CCCC3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CCCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.050 g), sodium hydrogen carbonate (0.081 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[(1-hydroxycyclopentyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.026 g) was added, and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 58 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.010 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0090 mL) were added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.0070 g, 23%).
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:15][C:16]#[N:17])[C:10](OCC)=[O:11])=[CH:5][CH:4]=1.N.CO>[Ni].CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:15][CH2:16][NH:17][C:10]2=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CC#N)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: O=C1NCCC1(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL stainless steel pressure bottle was charged with a Raney®-nickel 2800/water slurry (23.60 g, 402 mmol), followed by addition of the product from Example 25A (5.90 g, 16.9 mmol) and a solution of 7M NH3—CH3OH (30 mL)/CH3OH (120 mL). The reaction mixture was stirred at ambient temperature under an atmosphere of 30 psi H2 for 4 hours. The mixture was filtered through a nylon membrane and concentrated in vacuo. The crude product was slurried in 5% ethyl acetate/hexane, and the solid was collected by filtration to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.13 (s, 1H), 7.41-7.35 (m, 4H), 7.35-7.30 (m, 4H), 3.18 (t, J=6.4, 2H), 2.72 (t, J=6.4, 2H); MS (DCI+) m/z 323 (M+NH4)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH2:15]=[O:16].[ClH:17]>ClCCCl>[Cl:17][CH2:15][O:16][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: Cl
Reactant: C=O
Reactant: O=C1c2ccccc2C(=O)N1CCO
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1CCOCCl

Procedure:
A dispersion of N-(2-hydroxyethyl)phthalimide (19.1 g) and paraformaldehyde (3.0 g) in 1,2-dichloroethane (250 ml) was cooled in an ice-salt-acetone bath and saturated with dry hydrochloric acid with stirring. After 4 hours the mixture was dried over calcium chloride, filtered and evaporated under reduced pressure to give N-(2-chloromethoxyethyl)phthalimide (21.9 g), m.p. 69°-72° C. To a stirred solution of tris trimethylsilylguanine (16.5 g) in toluene (50 ml) was added N-(2-chloromethoxyethyl)phthalimide (17.0 g) and triethylamine (23 ml). The reaction mixture was heated at reflux under nitrogen for 29 hours, cooled and evaporated under reduced pressure giving a dark brown oil. The oil was digested in ethanol (400 ml) on a steam bath for 40 minutes, giving a solid which was collected and washed with ethanol and ether. It was recrystallized from 2-methoxyethanol to give 9-(2-phthalimidoethoxymethyl)guanine hydrate (14.4 g), m.p.>240° C. (dec.). A mixture of 9-(2-phthalimidoethoxymethyl)guanine hydrate (0.94 g), hydrazine (2 ml) and ethanol (100 ml) was heated at reflux with stirring for one hour. The reaction mixture was filtered hot, and the filtrate was cooled and evaporated under reduced pressure. Ethanol was added and the mixture re-evaporated. This was repeated three times. The residual solid was stirred with 3% aqueous acetic acid (50 ml) for 30 minutes and filtered. The solids were washed with water (15 ml), and the wash and filtrate combined. The combined wash and filtrate was evaporated under reduced pressure at<35° C. to a small volume, diluted with ethanol and evaporated to dryness. The pasty, white solid was dispersed in a small amount of ethanol and diluted with a few ml ether to give a granular solid which was collected, washed with ethanol and dried. Recrystallization from ethanol-water gave 9-(2-aminoethoxymethyl)guanine acetate monohydrate (0.43 g), m.p. (~135° C. melts and resolidifies) 174°-176° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[CH:29][C:28](=[O:32])[N:27]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:38]CCl>Cl.C(OCC)C>[ClH:38].[CH:33]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[C:30]([CH3:31])=[CH:29][C:28]2=[O:32])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cn3)ncc12
Reaction time: 48 h
Yield: 90.9 %

Procedure:
4-[6-(8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.093 g, 0.184 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl in diethyl ether (2 mL) was added and the resulting mixture was stirred for 2 days. Additional 2 N HCl was added and stirring was continued for 16 hours. The solvent was removed to give 8-cyclopentyl-5-methyl-2-(5-piperazin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.080 g, 90.9%). 1H NMR δ (400 MHz, DMSO-d6) 9.92 (s, 2H), 8.85 (s, 1H), 8.02 (d, J=2.9 Hz, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.78 (d, J=9.3 Hz, 1H), 6.33 (s, 1H), 5.79 (m, 1H), 3.40 (m, 4H), 3.22 (m, 4H), 2.39 (s, 3H), 2.20 (m, 2H), 1.91 (m, 2H), 1.74 (m, 2H), 1.56 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:21])[C@@H:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:22][CH3:23].Br[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:34][O-].[Na+].O>CO>[CH2:20]([S:17]([NH:16][C@@H:12]([CH:13]([CH3:15])[CH3:14])[C:11]([NH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:3]([O:22][CH3:23])[CH:4]=1)=[O:21])(=[O:19])=[O:18])[CH3:34]
Reactant: BrC/C=C/c1ccccc1
Reactant: COc1cc(CCNC(=O)[C@@H](NS(C)(=O)=O)C(C)C)ccc1O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OC/C=C/c2ccccc2)c(OC)c1)C(C)C

Procedure:
A mixture of (S)-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-2-methanesulfonylamino-3-methyl-butyramide (2.5 g), E-(3-bromo-propenyl)-benzene(1.5 g) and sodium methoxide (9 ml 1M solution in methanol) in methanol (30 ml) is heated to reflux for 4 hours. Upon cooling water (400 ml) is added. The mixture is extracted with ethyl acetate (2×300 ml). The organic layers are washed with brine (100 ml), dried (MgSO4) and evaporated. The resulting residue is purified by recrystallisation (ethyl acetate/hexane). E-(S)-2-Ethanesulfonylamino-N-{2-[3-methoxy-4-(3-phenyl-allyloxy)-phenyl]-ethyl}-3-methyl-butyramide is obtained, m.p. 128-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([O:12]C)=[O:11])=[O:4].[OH-].[K+].Cl>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([OH:12])=[O:11])=[O:4]
Reactant: COC(=O)C1CCCC1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1CCCC1C(=O)O
Temperature: 75 °C

Procedure:
Cyclopentane-1,2-dicarboxylic acid dimethyl ester (2.50 g, 13.4 mmol) was dissolved in methanol (2.5 mL) and a solution of potassium hydroxide (85% purity) (920 mg, 13.9 mmol) in methanol (4.0 mL) and water (0.5 mL) in a 25 mL round bottom flask. The reaction mixture was heated at 75° C. for 4 h. The reaction mixture was cooled to 0° C. and acidified to pH 2 with 2M HCl in water. The reaction mixture was diluted with water (100 mL) and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to give cyclopentane-1,2-dicarboxylic acid monomethyl ester as a faint-yellow liquid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23]([OH:25])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:29])=O>CN(C=O)C.C(Cl)Cl>[Cl:29][C:23]([CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])=[O:25]
Reactant: O=C(O)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a solution of 1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (1.2 mg, 3.6 mmol) and 2 drops DMF in DCM was added oxalyl dichloride (2 g, 15.9 mmol), resulting in bubbling of the solution. After the solution stopped bubbling, the reaction solution was concentrated to give the crude product, which was directly used for the next step.
Reaction SMILES: [NH2:1][C:2]([C:4]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:2]([C:4]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CCOCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C#N)CCOCC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(aminocarbonyl)tetrahydro-2H-pyran-4-yl-carbamate (C-25) and triethylamine (2.1 eq.) in dichloromethane was cooled to 0° C. and trifluoroacetic anhydride (1.1 eq.) was added dropwise under nitrogen. Stirring was continued for 1 hour allowing the mixture to reach room temperature. Volatiles were removed in vacuo and residue was taken up in ethyl acetate, washed with HCl 1N, brine and dried over Na2SO4. Evaporation gave a crude which was purified by flash chromatography on silica gel (eluent:petroleum ether:ethyl acetate=7:3) to give the title compound (C-26), colorless oil, as a 8:2 mixture of two rotamers by 1H NMR.
Reaction SMILES: C(O[BH-](O[C:11](=O)[CH3:12])OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:24][NH:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]3[CH:49]=[CH:48][C:47]4[CH2:46][CH2:45][CH2:44][NH:43][C:42]=4[N:41]=3)[CH2:36][CH2:35]2)[N:29]=[CH:28][N:27]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>O1CCCC1>[CH2:31]([CH:32]([CH2:11][CH3:12])[CH2:33][NH:15][CH:16]([CH2:24][NH:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([N:34]2[CH2:35][CH2:36][CH:37]([C:40]3[CH:49]=[CH:48][C:47]4[CH2:46][CH2:45][CH2:44][NH:43][C:42]=4[N:41]=3)[CH2:38][CH2:39]2)[N:29]=[CH:28][N:27]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH3:30]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(NCC(NCC(CC)CC)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reaction time: 0.17 h

Procedure:
75 mg (0.35 mmoles) of sodium triacetoxyborohydride in 6 ml of tetrahydrofuran is left under stirring for 10 minutes at TA. Then a mixture of 100 mg (0.208 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate and 0.228 mmoles of 2-ethyl-butylaldehyde in solution in 3 ml of tetrahydrofuran is added. The reaction mixture is stirred at ambient temperature for 4 hours 30 minutes. Then it is extracted with ethyl acetate after washing with a saturated solution of sodium bicarbonate. The organic phase obtained is dried over magnesium sulphate before being concentrated to dryness under reduced pressure (2 kPa). The residue is then chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane/methanol (80/20) 50-50. A mass my of expected product is obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C:12]2[NH:13][C:14]3[C:15]([N:38]=2)=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]=4[CH:37]=2)[CH:19]=3)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[O:29]1[C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:19]=[C:14]4[NH:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:38][C:15]4=[N:16][CH:17]=3)=[CH:37][C:24]=2[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1)OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 1,1-dimethylethyl 7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.49 g, 1.9 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the resulting solution was heated at 50° C. After 1 h the reaction mixture was concentrated and the residue was concentrated three times from ethyl acetate (30 mL) to afford phenylmethyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate as the bis-trifluoroacetate salt (0.48 g, 95% yield). MS (EI) for C23H21N5O3: 416 (MH+).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[ClH:7].[NH2:8][C:9]([NH2:11])=[O:10]>O>[OH:1][CH:2]([NH:8][C:9](=[O:10])[NH:11][CH:2]([OH:1])[C:3]([Cl:5])([Cl:4])[Cl:7])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cl
Reactant: NC(N)=O
Solvent: O
Product: O=C(NC(O)C(Cl)(Cl)Cl)NC(O)C(Cl)(Cl)Cl
Yield: 57 %

Procedure:
This compound has previously been prepared by Chattaway and James [Proc. Roy. Soc., A134 372 (1931)]. A mixture of chloral (162.2 g, 1.1 mole), H2O (100 ml), and concentrated HCl (150 ml) was stirred at 70°-80° C. Urea (30 g, 0.5 moles) was added all at once and the resulting mixture was stirred for 5 hours. The white precipitate which formed was filtered, and then washed with water until the pH of the wash water was 7. The product was then recrystallized from aqueous EtOH to give white needles; 57% yield, m.p. 193°-194° C.