Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>C(NC(C)C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[S:4]1[CH:5]=[CH:6][C:2]([C:9]#[C:8][CH2:7][OH:10])=[CH:3]1
Reactant: Brc1ccsc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: OCC#Cc1ccsc1
Yield: 48.2 %

Procedure:
To a suspension of bis (triphenylphosphine)-palladium (II) chloride (300 mg, 0.42 mmol) and copper (I) iodide (100 mg, 0.50 mmol) in diisopropylamine (100 ml) under nitrogen was added 3-bromothiophene (4.9 g, 30 mmol). After reflux under nitrogen for 1.5 h a solution of propargyl alcohol (3.0 g, 33 mmol) in diisopropylamine (50 ml) was added. After reflux for 5 h the reaction mixture was cooled, filtered and concentrated in vacuo. The residue was submitted to flash chromatography using ether/petroleum ether (1:1) as eluent to give 2 g (48%) of 3-(3-thienyl)-2-propyn-1-ol as a crude product.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.C([Si]([O:22][CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]#[CH:30])[CH:28]=1)(C)C)(C)(C)C.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1.CCCCCC.O>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH:30]=[C:29]([C:27]3[CH:28]=[C:24]([CH2:23][OH:22])[S:25][CH:26]=3)[O:1][N:2]=2)=[CH:5][CH:6]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: C#Cc1csc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CC(C)Cc1ccc(C(Cl)=NO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc(-c2cc(-c3csc(CO)c3)on2)cc1
Yield: 58.5 %

Procedure:
To a solution of N-hydroxy-4-isobutylbenzenecarboximidoyl chloride (0.50 g, 2.4 mmol) that was obtained in Example 9 (9f) and t-butyl[(4-ethynyl-2-thienyl)methoxy]dimethylsilane (0.72 g, 2.8 mmol) that was obtained in Example 9 (9d) in ethyl acetate (10 ml) was added triethylamine (0.40 ml, 2.8 mmol) at 0° C. with stirring, and the resulting mixture was stirred at room temperature for 18 hours. After stirring, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in tetrahydrofuran (15 ml) was added tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 2.8 ml, 2.8 mmol) at 0° C. with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to the residue obtained was added a mixed solvent of ethyl acetate and hexane (1:3) with stirring, and the solid precipitated was collected by filtration using a Kiriyama funnel and washed with the same solvent to afford the title compound (0.44 g) in a yield of 59% as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3](C(F)(F)F)[C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[K+]>O>[F:1][C:2]([F:13])([F:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C(F)(F)F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)CC(F)(F)F
Yield: 76.1 %

Procedure:
To a solution of 105 g (0.5 mol) of methyl 2-(trifluoromethyl)-3,3,3-trifluoropropionate in 250 ml of water, a solution of 150 g (1.5 mol) of potassium acetate in 500 ml of water was added dropwise and the mixture was refluxed for 5 hours. After separation of the oily layer, extraction was made from the water layer that was left using methylene chloride. The oily layer and extracted fraction were joined and dried. After evaporation of methylene chloride under atmospheric pressure, purification by distillation was performed to give methyl 3,3,3-trifluoropropionate (TFPE) (54.07 g, 76%). Its analysis gave the following data:
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][CH3:26]>>[CH2:1]([CH:8]([CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])[C:9]([O:11][CH2:24][CH2:25][CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Reactant: CCCO
Product: CCCOC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1

Procedure:
To 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (100 mg) were added propanol (2 ml) and boron trifluoride diethyl ether complex (12 μl) with stirring. After the mixture was stirred at room temperature for 24 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed succecively with saturated sodium bicarbonate solution and brine, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 106 mg of propyl 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[O:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[O:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(Br)o1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)o1

Procedure:
1-(5-(4-(Trifluoromethyl)phenyl)fur-2-yl)ethanone is prepared from 4-trifluoromethylbenzeneboronic acid and 5-bromo-2-acetylfuran according to general procedure A.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:5]2[S:10][C:9]([Cl:11])=[CH:8][C:6]=2[N:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=1>C(O)CCC>[Cl:11][C:9]1[S:10][C:5]2[C:4]([C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[O:13])=[N:3][C:2]([NH:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[N:7][C:6]=2[CH:8]=1
Reactant: O=C(c1cccs1)c1nc(Cl)nc2cc(Cl)sc12
Reactant: NCc1cccnc1
Solvent: CCCCO
Product: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Temperature: 100 °C
Yield: 38 %

Procedure:
A stirred solution of Example 4 (5 g, 16 mmol) in n-butanol (120 ml) was treated with 3-picolylamine (8.1 ml, 80 mmol) and heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature, reduced in vacuo and the residue purified by silica gel (100 g) column chromatography (3% MeOH/DCM) affording the title compound in 38% yield, >95% purity. LC-MS m/z=387.0 [M+H]+; RT=3.30 min; LC-MS method 1.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([OH:21])([C@@H:15]([CH2:16]OC(N)=O)[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[N:22]([CH3:23])[C@H:12]1[CH2:11]3.CC(C)([O-])C.[K+].C(=O)=O>O1CCOCC1>[CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([OH:21])([C:15](=[CH2:16])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[N:22]([CH3:23])[C@H:12]1[CH2:11]3
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@H](COC(N)=O)[C@@]1(O)[C@@H]3[C@H](CN21)N3C
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1C2=C(C(=O)C(C)=C(OC)C2=O)N2C[C@H]3[C@H](N3C)[C@]12O
Temperature: 25 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
In this example, 100 mg of mitomycin B is dissolved in 5 ml of dioxane. To this solution, 100 mg of potassium t-butoxide is added and the mixture is stirred at room temperature for 2 days. The reaction mixture is then neutralized with an excess amount of dry ice and subjected to filtration. The filtrate is concentrated under reduced pressure and the residue is then subjected to silica gel column chromatography using a mixed solvent of acetone and chloroform (1:4) (volume ratio as is the same hereinafter) as a developer. Fractions of eluate which have a high Rf value and are blue are combined and concentrated under reduced pressure. The residue is crystallized from acetone and petroleum ether to obtain 14 mg of the desired compound (yield 17.0%) as purplish black needle-like crystals having the following physical properties.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([CH3:18])=[C:12]3[N:11]=[C:10]2[CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.[H-].[Na+].BrCC1C=CC(/[CH:32]=[C:33](/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)\[C:34]([O:36][CH3:37])=[O:35])=CC=1>CN(C=O)C>[C:34](/[C:33](/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[CH:32]\[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([CH3:18])=[C:12]3[N:11]=[C:10]2[CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1)([O:36][CH3:37])=[O:35]
Reactant: COC(=O)/C(=C\c1ccc(CBr)cc1)c1ccccc1
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(/C=C(\C(=O)OC)c2ccccc2)cc1
Yield: 37.8 %

Procedure:
To a solution of 30 mg (0.171 mmol) of 2-propyl-7-methylimidazo[4,5-b]pyridine (Example 2, Step D) dissolved in 1 mL of dry DMF was added 11 mg of a 60% oil dispersion of NaH (1.5 eq) and the reaction mixture was stirred under an N2 atmosphere. After stirring at room temperature for 30 minutes the product from Step C (27.4 mg, 0.082 mmol) dissolved in 0.5 mL DMF was added via syringe. The reaction mixture was quenched with saturated NH4Cl solution, and the solvent was removed under in vacuo. The residue was dissolved in EtOAc and washed with H2O and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 50% ethyl acetate/hexane to provide 13.2 mg (38%) of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:19]=[CH:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([CH3:20])=[N:10]3)[N:7]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[N+:1]([C:15]1[CH:16]=[C:17]2[C:8]([N:7]=[C:6]([CH3:5])[CH:19]=[CH:18]2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([CH3:20])=[N:10]2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2cc([N+](=O)[O-])c3ccc(C)nc3c2n1
Temperature: 115 °C

Procedure:
An acid mixture composed of 5 mL nitric acid (GR (Guaranteed Reagent) grade undiluted solution from Wako Pure Chemical Industries Ltd.) and 10 mL sulfuric acid (GR grade undiluted solution from Wako Pure Chemical Industries Ltd.) was added to 0.5 g of 2,9-dimethyl-1,10-phenanthroline (Wako Pure Chemical Industries Ltd.) and the mixture was heated to 115° C. for 1 hour. To the resulting solution, 100 g of ice was added and the pH of the chilled solution was adjusted to 8.0 by the addition of sodium hydroxide. The resulting precipitate was separated by filtration and dried at 110° C. to give 5-nitro-2,9-dimethyl-1,10-phenanthroline as shown by the formula (B) in FIG. 1.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH:30]([CH3:33])[CH:31]=O)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH:30]([CH3:33])[CH2:31][N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:13](=[CH:18][CH:19]=3)[C:14](=[O:17])[O:15][CH2:16]4)[CH2:3][CH2:4]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: COc1cc(C(C)C=O)ccc1C#N
Agent: Cl
Product: COc1cc(C(C)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[1-methyl-2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 420.5 [M+1]+. (0.28 μM)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([NH2:77])[CH:72]=1)([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:72]=1)([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-amino benzoic acid t-butyl ester (Aldrich, 50 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 5% EtOAc/methylene chloride) to give a white solid. 80 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: NCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile and benzylamine in DME. ES-MS m/e (%): 303 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[NH2:15].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[N:25]=[C:26]=[S:27]>CO>[CH2:9]([N:8]([CH2:12][CH2:13][CH3:14])[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:15][C:26]([NH:25][C:18]2[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][C:19]=2[CH3:24])=[S:27])[CH:4]=1)[CH2:10][CH3:11]
Reactant: CCCN(CCC)c1ccc(C)c(N)c1
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Solvent: CO
Product: CCCN(CCC)c1ccc(C)c(NC(=S)Nc2c(C)cc(C)cc2C)c1
Yield: 70.1 %

Procedure:
A mixture of 4-Methyl-N1,N1-dipropyl-benzene-1,3-diamine (200 mg, 0.970 mmol) and 2,4,6-trimethylphenylisothiocyanate (215 mg, 1.21 mmol) in methanol (2 ml) was refluxed for 18 h. The solvent was evaporated under vacuum. The residue was triturated with methanol. The solid was collected by filtration and washed with methanol to afford 261 mg of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4].[C:29]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br)#[N:30].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([C:29]#[N:30])[CH:32]=3)[C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)[nH]c(=O)c21
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(Cc3cccc(C#N)c3)c(=O)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
100 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 1.2 ml of N,N-dimethylformamide, and then 97 mg of 3-cyanobenzyl bromide and 68 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for 12 hours. Then, a saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 71 mg of the title compound.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>CO>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:14]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CO
Product: ClCc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 57 %

Procedure:
2.33 g of thiobenzamide was dissolved in 20 ml of dry methanol, and 2.16 g of 1,3-dichloroacetone was added thereto at room temperature and then heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and ice water was added to the remaining product, which was then neutralized with an aqueous solution of sodium hydrogen carbonate. The resulting product was extracted with ethyl acetate, washed with saturated saline, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 2.03 g of 4-chloromethyl-2-phenylthiazole, was obtained from the fraction eluted with chloroform/n-hexane=1/2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([NH2:39])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[NH2:39][C:37]1[N:36]=[CH:35][N:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:40])[NH:16][C:9]4[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:38]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(N)ncn2)c1
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(N)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (103 mg, 0.4 mmol) and 3-[3-(6-amino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K53) (138 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (126 mg).
Reaction SMILES: [CH2:1]([N:3]1[C@@H:11]2[C:6]3=[C:7]([CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]3[C@H:4]1[CH2:24][CH2:25][CH3:26])[C:8]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH2:10]2)[CH3:2].CCOCC>CC(C)=O>[CH2:1]([N:3]1[C@H:11]2[C:6]3=[C:7]([CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]3[C@@H:4]1[CH2:24][CH2:25][CH3:26])[C:8]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH2:10]2)[CH3:2]
Reactant: CCC[C@@H]1c2cc(C)cc3c2[C@H](Cc2ccc(OC)c(OC)c2-3)N1CC
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCC[C@H]1c2cc(C)cc3c2[C@@H](Cc2ccc(OC)c(OC)c2-3)N1CC

Procedure:
74.3 g (211 mM) of (±)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-2-methyl-4-n-propyl-dibenz[cd,f]indole are dissolved in 600 ml acetone and a solution of 81.67 g (211 mM) of (-)-di-O,O'-p-toluoyl-L-tartaric acid monohydrate in 300 ml acetone is added with stirring. The mixture is further stirred for one hour at room temperature, a total of 1 liter ether being added in portions during this period. The resultant precipitate is filtered off, washed with ethyl acetate until it remains light yellow, and dried.
Reaction SMILES: [OH-:1].[K+].[C:3]([NH:6][C:7]1[C:8]([I:31])=[C:9]([C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:10]([I:22])=[C:11]([C:20]=1[I:21])[C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])(=[O:5])[CH3:4].B(O)(O)O.Cl>O.CC(O)(C)C>[C:3]([N:6]([CH2:11][CH:20]([OH:1])[CH2:7][NH2:6])[C:7]1[C:20]([I:21])=[C:11]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:10]([I:22])=[C:9]([C:8]=1[I:31])[C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: [OH-]
Agent: Cl
Agent: OB(O)O
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)N(CC(O)CN)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Yield: 19 %

Procedure:
To a stirred solution of Water/tBuOH (2:1, 8 mL:10 mL) and KOH (0.73 g, 13 mmol, 1.2 eq was added at 40° C. 5-Acetylamino-N,N′-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (8.1 g, 11 mmol). To the clear solution was then added boric acid (0.47 g, 8 mmol, 0.7 eq). The mixture was cooled to room temperature and the pH adjusted to pH 12.6-13.0 with KOH. t-Butyl n-(2-oxiranyl-methyl)carbamate (0.996 g, 8 mmol, 0.7 eq) was added, and the pH was measured several times and adjusted to 12.6-13.0. The mixture was stirred over the weekend. An aqueous solution of HCl was then added until pH 4. The reaction mixture was evaporated to dryness. The product was purified by C18 column chromatography eluting with MeOH/Water to give 5-[Acetyl-(3-amino-2-hydroxy-propyl)-amino]-N,N′-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (2.09 mmol, Yield=19%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[B:10](OC)([O:13]C)[O:11]C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:13])[OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
In a separate reaction vessel, 40 mL of tetrahydrofuran was cooled to -78° C., and the Grignard reagent of 3,5-difluorophenyl bromide and a solution of 11.3 grams (0.109 mole) of trimethyl borate in 15 mL of tetrahydrofuran were added simultaneously dropwise in an effort to provide an equimolar addition of each. An additional 115 mL of tetrahydrofuran was added during the additions to dilute the thickening reaction mixture. The completion of additions required about 15 minutes. After this time the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 300 mL of an aqueous dilute solution of hydrochloric acid. The resultant mixture was extracted with two 150 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 13.6 grams of 3,5-difluoro-phenylboronic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:17]([NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[C:4](=[O:9])[N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1nc(O)ncc1F
Solvent: CN(C)C=O
Product: Nc1nc(=O)n(C(=O)Nc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol* (0.25 g, 1.94 mmol) in dry N,N-dimethylformamide (DMF; 5 mL) was added phenyl isocyanate (0.231 mL, 2.13 mmol), and the mixture was stirred at room temperature for 1 h. The suspension was suction filtered, and washed with diethyl ether (Et2O; 3×10 mL). The resulting solid was air-dried overnight to yield 4-amino-5-fluoro-2-oxo-N-phenylpyrimidine-1(2H)-carboxamide (0.32 g, 66%) as a white solid: mp 275-277° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.63 (s, 1H), 8.43 (d, J=7.25 Hz, 1H), 8.35 (s, 1H), 7.55 (d, J=7.58 Hz, 2H), 7.37 (t, J=7.58 Hz, 2H), 7.13 (t, J=7.25 Hz, 1H); ESIMS m/z 247.1 ([M−H]−).