Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][C:6]([CH3:33])=[C:5]([CH3:34])[N:4]=2.[CH3:35][NH2:36]>>[CH3:35][NH:36][C:11]([C:10]1[CH:9]=[C:8]2[C:3](=[C:2]([Cl:1])[C:15]=1[NH:14][C:13]([C:16]1[N:17]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:12])[N:4]=[C:5]([CH3:34])[C:6]([CH3:33])=[N:7]2)=[O:32]
Reactant: Cc1nc2cc3c(=O)oc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)nc3c(Cl)c2nc1C
Reactant: CN
Product: CNC(=O)c1cc2nc(C)c(C)nc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 68 %

Procedure:
See example H3 for the reaction conditions using 9-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-6,7-dimethyl-3-oxa-1,5,8-triaza-anthracen-4-one as starting material and 2 equivalents of methylamine (40% in H2O). After 10 hours reaction time and purification by flash chromatography on silica gel, a white solid is obtained in 68% yield. m.p.: 221-224° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([N:18]=[C:19]=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[C:8]([C:7]1[C:2]([NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cccnc1N
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cccnc1NC(=O)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 2-amino-3-cyanopyridine (300 mg, 2.5 mmol) in 1.4-dioxane (5 mL) was added benzoyl isocyanate (370 mg, 2.5 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitation was collected by filtration, washed with EtOAc/Hexanes (1:4), and dried under vacuum to give N-(3-cyanopyridin-2-ylcarbamoyl)benzamide as a white solid (360 mg, 54%). MS 266 (MH+).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH2:19](Cl)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCC=Cc1ccccc1
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NCC=Cc1ccccc1)c1ccccc1
Yield: 46.5 %

Procedure:
To a solution of (S)-α-methylbenzylamine (1) (0.500 g, 4.13 mmol) in toluene (20 ml) were added N-ethyldiisopropylamine (0.719 ml, 4.13 mmol) and cinnamyl chloride (0.575 ml, 4.13 mmol). The mixture was refluxed overnight, after which the toluene was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (30 ml) and the organic layer was washed with brine (30 ml), dried (magnesium suphate) and removed under reduced pressure to afford a yellow oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:4) to give the title compound (4) as a colourless oil (0.456 g, 47%). δH (200 MHz; CDCl3) 7.41-7.20 (10H, m, Ph), 6.50 (1H, d, J=15.9, PhCH=CH), 6.30 (1H, dt, J=15.9 and 6.1, PhCH=CH), 3.88 (1H, q, J=6.6, PhCHCH3), 3.29 (2H, d, J=6.5, NCH2), 1.56 (1H, br s, NH), 1.42 (3H, d, J=6.8, PhCHCH3).
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([Cl:9])=[O:8].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([Cl:1])[C:12]=1[CH3:13])[C:7]([Cl:9])=[O:8]
Reactant: Cc1ccc(C(=O)Cl)cc1Cl
Reactant: ClCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 4 °C
Reaction time: 6 h

Procedure:
A jacketed kettle was equipped with a chiller, overhead stirrer, thermometer, and connections to a chlorine tank and a caustic scrubber. The kettle was charged with the previously prepared 3-chloro-4-methylbenzoyl chloride (1 part) and dichloromethane (6.8 parts). Aluminum trichloride (0.8 parts) was added, and the resulting red-brown mixture was cooled with agitation to 3-5° C. Chlorine (0.37 parts) was introduced at a sufficient rate to keep the reaction temperature below 10° C. The reactor was held at 0-5° C. for 6 hours. The reaction mixture was purged with nitrogen and slowly quenched by transfering into an agitated and chilled hydrochloric acid solution (4.4 parts) while maintaining the temperature below 5° C. Agitation was stopped and the lower organic layer was recovered. The solvent was removed by distillation.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][OH:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:45](I)[CH:46]=[CH2:47]>C(OCC)(=O)C.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:47][CH:46]=[CH2:45])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6.86 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate [Step A of Example 14], 3.51 g of potassium carbonate, 15 ml of dimethylformamide and 7 ml of allyl iodide was stirred under an inert atmosphere at room temperature for 5 hours and then 250 ml of water and 150 ml of ethyl acetate were added thereto with stirring. The mixture was decanted and the aqueous phase was washed and reextracted with ethyl acetate. The extracts were dried, vacuum filtered and evaporated to dryness. The residue was taken up in ethanol and crystallization was started. The mixture was cooled in an ice bath with stirring for half an hour and was then vacuum filtered. The crystals were rinsed with ethanol to obtain 4.72 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-propenyloxyimino)-acetate. 215 mg of the product were dissolved in 2 ml of ethanol and 2 ml of methylene chloride and the mixture was filtered. The filtrate was concentrated and diluted with ethanol. Crystallization was effected in an ice bath and the mixture was vacuum filtered. The crystals were rinsed with ethanol and dried to obtain 70 mg of the pure product which melted at 90° C. (pasty) and 160° C. (pure).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:20][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][OH:23])[CH:6]=1.C(N(CC)CC)C.[C:38](Cl)(Cl)=[O:39].CCOC(C)=O>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]2[C@@H:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][O:23][C:38]2=[O:39])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H](CO)c2ccccc2)c1
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)OC[C@@H]2c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
To {3-(4-Bromo-2-[((S)-2-hydroxy-1-phenyl-ethylamino)-methyl]-phenoxy}-phenyl)-acetic acid methyl ester (0.43 mmol) and triethylamine (0.18 mL, 1.29 mmol) in toluene (1.5 mL) at 0° C. was added phosgene (1.9M in toluene; 0.23 mL, 0.43 mmol). The reaction was stirred for 15 minutes at 0° C., until no starting material was seen by analytical LCMS, and then worked-up with 5% brine and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give the desired product (0.086 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][OH:4].[N:15]#[C:16]Br>>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)=[CH:13][CH:12]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCOc1ccc(Cl)cc1
Product: NC1=N[C@@H](CCOc2ccc(Cl)cc2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(4-chloro-phenoxy)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-chloro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 240.9 ([M+H]+))
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:33][O:34][CH2:35][CH2:36][NH:37]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[N:14]3[C:19]4[CH:20]=[CH:21][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=[CH:16][C:15]=23)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1>[NH2:37][CH2:36][CH2:35][O:34][CH2:33][C:13]1[N:14]2[C:19]3[CH:20]=[CH:21][NH:22][C:18]=3[N:17]=[CH:16][C:15]2=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:10][CH:9]=2)[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc(COCCNC(=O)OCC4c5ccccc5-c5ccccc54)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(-c2nc(COCCN)n3c2cnc2[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 2-((3-(4-(2-hydroxypropan-2-yl)phenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methoxy)ethylcarbamate (0.030 g, 0.040 mmol, Preparation #AW.1) in 1,4-dioxane (1 mL) was added NaOH (5.0 N aqueous, 0.040 mL, 0.20 mmol). The mixture was heated at about 70° C. for about 4 h. The mixture was then concentrated under reduced pressure, dissolved in MeOH/DMSO (1:1) (2 mL) and purified via reverse phase preparatory HPLC (Table 2, Method n). The desired fractions were collected and concentrated under reduced pressure. The residue was dissolved in water (4 mL) and lyophilized for 16 h to give 2-(4-(1-((2-aminoethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (6.5 mg, 44%): LC/MS (Table 2, Method a) Rt=1.30 min.; MS m/z: 364 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-].N.CCO>>[NH2:28][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: COc1cccc(C2CC3(N=C(SC)N(C)C3=O)c3cc(Br)ccc3O2)c1
Agent: N
Agent: [I-]
Solvent: CCO
Product: COc1cccc(C2CC3(N=C(N)N(C)C3=O)c3cc(Br)ccc3O2)c1
Yield: 75.7 %

Procedure:
A solution of 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (65 mg, 0.146 mmol), NH4I (42.26 mg, 0.3 mmol) in a solution of NH3/EtOH (2 mL, 8 N) was heated at 120° C. in a tube under microwave reactor for 2 h. After cooling, the mixture was concentrated in vacuum to give 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (46 mg, 80%).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:22][CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(CBr)c1cccnc1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1c(OCC(=O)c2cccnc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (600 mg, 2 mmol) (HBr salt) was added to a mixture of 2-amino-3-nitrophenol (300 mg, 2 mmol) and potassium carbonate (400 mg, 3 mmol) in acetone (30 mL, 400 mmol) at room temperature. The reaction was stirred at room temperature for 18 h, was diluted with water, and was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 2-(2-amino-3-nitrophenoxy)-1-pyridin-3-ylethanone (0.35 g, 60%). LCMS calculated for C13H12N3O4 (M+H)+: m/z=274.1. found: 274.1.
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[CH3:7][O:8][C:9]12[CH2:17][CH:13]3[CH2:14][CH:15]([CH2:16]1)[C:11]([C:18](=[O:20])C)([CH2:12]3)[CH2:10]2.CC(O)=[O:23]>O1CCOCC1.O>[CH3:7][O:8][C:9]12[CH2:17][CH:13]3[CH2:14][CH:15]([CH2:16]1)[C:11]([C:18]([OH:20])=[O:23])([CH2:12]3)[CH2:10]2
Reactant: COC12CC3CC(C1)C(C(C)=O)(C3)C2
Reactant: CC(=O)O
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Solvent: O
Product: COC12CC3CC(C1)C(C(=O)O)(C3)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.6 %

Procedure:
To a mixture of NaOH (5.8 g, 147 mmol), H2O (40.0 mL) and 1,4 dioxane (10 mL) at ice bath temperature was added Br2 (2.8 mL, 55.0 mmol) and stirred for 5 minutes. The resulting hypobromite solution was added drop-wise to a stirred solution of 1-(1-methoxytricyclo[3.3.1.03,7]non-3-yl)ethanone obtained from step III (1.9 g, 9.8 mmol), in 1,4-dioxane (10 mL) at ice bath temperature. The reaction mixture was gradually warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to ice bath temperature and AcOH (3.9 mL, 65.7 mmol) were added. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-methoxytricyclo[3.3.1.03,7]nonane-3-carboxylic acid (1.3 g) in 72% yield. m/z (M+1), 197; 1H NMR (CDCl3) 300 MHz δ 3.30 (s, 3H), 2.78-2.70 (m, 1H), 2.57-2.48 (m, 1H), 2.38-2.28 (m, 1H), 2.11-2.0 (m, 2H), 1.86-1.69 (m, 5H), 1.59-1.51 (m, 2H).
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: Oc1cccc(Cl)c1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cccc(Cl)c2)s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
5-Nitro-thiophene-2-carbonitrile (5.00 g, 32.5 mmol), 3-chloro-phenol (6.90 mL, 65.0 mmol) and potassium carbonate (13.4 g, 97.5 mmol) were suspended in dimethylsulfoxide (50 mL), and the mixture was stirred at 60° C. for 4 hours. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with water twice, and further washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (5.56 g, 23.6 mmol, 73%) was obtained as a pale yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([NH:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC2CC2)cc1
Temperature: 80 °C
Yield: 57.9 %

Procedure:
A mixture of ethyl 4-(cyclopropylamino)-benzoate (0.188 g, 0.916 mmol, CASRN 112033-48-4), 1 M NaOH (1.832 mL, 1.832 mmol) and EtOH (5 mL) was stirred and heated to 80° C. for 2 h. The EtOH was evaporated and the residue diluted with H2O, adjusted to pH ca. 2 and the resulting precipitate filtered, washed with water and air dried to afford 94 mg of 4-(cyclopropylamino)-benzoic acid (336) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)CC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][CH:12]([OH:11])[CH2:13][CH2:14]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Solvent: CCCO
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a suspension of 1.0 g (6.3 mmol) of 2-chloro-5-nitropyridine in 20 mL of n-propanol was added 1.9 g (18.9 mmol) of 4-hydroxypiperidine, and the mixture was stirred for 1.5 hours at 100° C. After cooling the reaction mixture, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to give 1.37 g (97%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([CH3:38])([CH3:37])[CH2:9][C@@:10]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.N1C=CC=CC=1.N>CN(C)C=O>[CH3:1][N:2]([CH3:6])[C:3]([N:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]3[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:37])[CH3:38])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:15][C:14]3=[O:16])[CH3:18])=[CH:24][CH:23]=2)[CH2:26][CH2:27]1)=[O:4]
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(=O)Cl
Agent: N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(C2CCN(C(=O)N(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylcarbamoyl chloride (26 μL) was added to a solution of (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (120 mg) and pyridine (40 μL) in N,N-dimethylformamide (2 mL) at room temperature. The solution was stirred at room temperature for 5 h, before another portion of dimethylcarbamoyl chloride (26 μL) and pyridine (20 μL) were added. The solution was stirred at room temperature overnight. Then, diluted aqueous ammonia solution was added and the resulting mixture was concentrated under reduced pressure. The residue was purified by HPLC on reversed phase (MeOH/H2O/NH3) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[C@@H:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)[NH:5][C:4]1=[O:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[C@@H:6]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[CH:12]=2)[NH:5][C:4]1=[O:21])(=[O:24])[CH3:23]
Reactant: Cn1cc(C[C@H]2NC(=O)[C@@H](CO)NC2=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1NC(=O)[C@@H](Cc2cn(C)c3ccccc23)NC1=O
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A mixture of (3R,6R)-3-hydroxymethyl-6-(1-methylindol-3-ylmethyl)-piperazine-2,5-dione (0.10 g), dry pyridine (1.0 ml) and acetic anhydride (0.08 g) was heated at 100° C. for 1 hour. After the mixture was cooled to ambient temperature, the pricipitated mass was collected, washed with pyridine and then ethanol, and dried to give (3R,6R)-3-acetoxymethyl-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (61.8 mg).
Reaction SMILES: C(C1C=CC([C:11]2[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](C)=[N:16]3)=CC=1)(C)(C)C.F.F.F.C(N(CC)CC)C>C1COCC1>[OH:21][C:18]1[CH:19]=[CH:20][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: Cc1ccc2c(-c3ccc(C(C)(C)C)cc3)ccc(O[Si](C)(C)C(C)(C)C)c2n1
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.6 %

Procedure:
To a 300 mL flask was added 6.7 g of 5-(4-t-butyl-phenyl)-2-methyl-8-t-butyldimethylsiloxyquinoline and 100 ml dry THF. The mixture was stirred under nitrogen while 13.5 ml triethylamine trihydrofluoride (Aldrich) was added in 5 portions over 30 min. The reaction mixture was stirred at room temperature for 2 h and the solvents removed in vacuo. The resulting oil was purified by silica chromatography, first eluting with 15% dichloromethane in hexanes and then collecting the product by elution with 50% dichloromethane in hexanes to give 4.33 g of the desired product quinaldine 2a as a colorless solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.CN1CCCC1.Br[C:34]1[CH:35]=[C:36]([O:57][CH3:58])[C:37]([NH:40][C:41](=[O:56])[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([S:48]([N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)(=[O:50])=[O:49])[CH:43]=2)=[N:38][CH:39]=1>C(OCC)(=O)C.[Cu]Cl>[CH3:58][O:57][C:36]1[C:37]([NH:40][C:41](=[O:56])[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([S:48]([N:51]3[CH2:52][CH2:53][CH2:54][CH2:55]3)(=[O:50])=[O:49])[CH:43]=2)=[N:38][CH:39]=[C:34]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:35]=1
Reactant: COc1cc(Br)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: Oc1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Oc2ccccc2)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 7.8 %

Procedure:
Phenol (21.4 mg), cesium carbonate (74.0 mg), copper(I) chloride (11.2 mg) and 2,2,6,6-tetramethylheptane-3,5-dione (2.1 mg) were added to an N-methylpyrrolidine (1.0 mL) solution of the compound (50.0 mg) obtained in Example 109 (Step 1), and with irradiation with microwaves, this was stirred at 180° C. for 20 minutes. The reaction liquid was diluted with ethyl acetate, and washed with water. The organic layer was dried with sodium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified through reversed-phase HPLC (0.1% TFA acetonitrile/H2O=from 10% to 90%, gradient), and further purified through preparative thin-layer chromatography (NH silica gel, methanol/chloroform=10%) to give the entitled compound (4.0 mg, 8%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2cnccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cnc2cnccn12
Temperature: 50 °C
Yield: 91.7 %

Procedure:
A mixture of 3-bromoimidazo[1,2-a]pyrazine (0.15 g, 0.76 mmol; prepared according to J. Bradac, et al. J. Org. Chem. (1977), 42, 4197-4201), 0.09 g (0.91 mmol) of ethynyltrimethylsilane, 0.044 g (0.038 mmol) of Pd(PPh3)4, 0.014 g (0.076 mmol) of CuI, and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.15 g of product: 216 m/z (M+H).