Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][C:16]([F:19])([F:18])[F:17].FC(F)(F)C(O)=O.O>C(Cl)(Cl)Cl>[OH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][C:16]([F:17])([F:18])[F:19]
Reactant: COCOc1ccc(C(=O)OC)cc1OC(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(O)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
Methyl 4-methoxymethoxy-3-trifluoromethoxybenzoate (590 mg) was dissolved in chloroform (10 mL), and trifluoroacetic acid (5 mL) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the solution, and then the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was washed with n-hexane to obtain the title compound (346 mg) as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=[O:9].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:7][N:6]1[C:2]([NH:1][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([CH:8]=[O:9])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(C=O)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(C=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 92 %

Procedure:
To a suspension of 5-amino-1-methylpyrazole-4-carbaldehyde (25 g, 200 mmol) and triethylamine (22.2 g, 220 mmol) in dichloromethane (500 ml) was added triphenylmethyl chloride (61.3 g, 220 mmol) at room temperature. The mixture was stirred at room temperature for 70 hours. The reaction mixture was washed with successively 10% aqueous citric acid solution, brine and 10% aqueous sodium hydrogencarbonate solution. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate to give 1-methyl-5-triphenylmethylaminopyrazole-4-carbaldehyde (67.6 g) as a colorless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>CN(C=O)C>[C:3]1([CH2:2][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc2ccccc12
Yield: 98.8 %

Procedure:
To a solution of 1-chloromethyl-naphthalene (8.83 g, 50 mmol) in DMF (90 mL) was added phthalimide potassium salt (11.1 g, 60 mmol). The resultant solution was stirred at 100° C. overnight. The mixture was poured into ice-cold water and the precipitate was collected, washed with small amount of methanol and dried under vacuo to give 2-naphthalen-1-ylmethyl-isoindole-1,3-dione 52 (14.2 g, 99% yield). This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:10]2[C:5](=[CH:6][C:7]([N+:23]([O-])=O)=[C:8]([N:11]([CH3:22])[C:12](=O)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]1=[O:31]>C(Cl)Cl.CO>[CH3:22][N:11]1[C:8]2=[CH:9][C:10]3[C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:5]=3[CH:6]=[C:7]2[N:23]=[C:12]1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N(C)C(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Solvent: CO
Solvent: ClCCl
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(CCc1ccccc1)n3C

Procedure:
1,7,7-Trimethyl-5-pentyl-2-phenethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one is prepared from crude N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-N-methyl-3-phenyl-propionamide as described in Example 3b. The desired compound (78 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (98:2).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)[NH2:24]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: OCc1ccc(Cn2ccc3ncnc(Cl)c32)cc1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OCc1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 140 °C
Yield: 93 %

Procedure:
{4-[(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol (354 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (488 mg) were dissolved in 1-methyl-2-pyrrolidone (2.58 mL), and the mixture was stirred with heating at 140° C. for 2 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL) and partitioned with saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (588 mg) as a powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][N:15]=1.N>>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:18]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: N#Cc1cccc(-c2noc(-c3ccc(Cl)nc3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 2 H), 8.17 (m, 1 H), 8.4 (m, 1 H), 8.43 (d, J=1.7 Hz, 1 H), 8.6 (m, 1 H), 9.25 (d, J=1.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 283 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([N:11]=[C:12](SC)[S:13][CH3:14])#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:9]([N:11]=[C:12]([N:5]1[CH2:6][CH2:7][O:8][CH:3]([CH3:2])[CH2:4]1)[S:13][CH3:14])#[N:10]
Reactant: CSC(=NC#N)SC
Reactant: CC1CNCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=NC#N)N1CCOC(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of 2-methylmorpholine hydrochloride (1.0 g, 9.9 mmol), dimethyl cyanocarbonimidodithioate (1.45 g, 9.9 mmol) and sodium carbonate (0.2 g, 1.9 mmol) in ethanol (50 mL) was stirred at ambient temperature overnight. The reaction mixture was concentrated and purified through silica gel chromatography to give the desired product (1.25 g, 63%). LC-MS: 200 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=O.[K+].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])C=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1)([O-:11])=[O:10].C(OCl)(C)(C)C.Cl>CN(C)C=O.CS(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]1[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C([O-])C(F)(F)F
Agent: CC(C)(C)OCl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(C(F)(F)F)c([N+](=O)[O-])c1
Yield: 40 %

Procedure:
A mixture of potassium trifluoroacetate (210 mg, 1.4 mmol and 1,3,5-trinitrobenzene (100 mg, 0.47 mmol) in one mL of N,N-dimethylformamide (DMF) or in one mL of dimethylsulfoxide (DMSO) was heated at 150° C. for one hour. A deep red solution of a Meisenheimer complex of formula (II) above (Z=nitro; Q=trifluoromethyl; R and R'=H; M=K; and n=1) was obtained. The structure of the complex was verified by NMR spectroscopy. Oxidation of a DMF solution of this complex by dropwise addition of tert-butylhypochlorite until the red color disappeared (about seven drops) followed by aqueous workup (10 mL of 1M HCl, extracted with three portions of diethyl ether afforded an oil. This was purified by preparative thin layer chromatography (one 2 mm silica gel plate eluted with 50% petroleum ether/50% dichloromethane) to give 53 mg (40% yield) of 1-trifluoromethyl2,4,6-trinitrobenzene.
Reaction SMILES: [Na].Cl.[CH:3]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4]1.C([O:11][C:12]([CH:14]1[CH2:18][CH2:17][N:16]=[C:15]1OCC)=O)C.Cl>CO.O>[CH:3]1([C:6]2[N:8]=[C:12]([OH:11])[C:14]3[CH2:18][CH2:17][NH:16][C:15]=3[N:7]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1CCN=C1OCC
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: Oc1nc(C2CC2)nc2c1CCN2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Sodium (0.417 g, 18.1 mmol) is dissolved in methanol (65 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (2.19 g, 18.1 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo to 30 ml. This free base is added to a solution of sodium (0.834 g, 36.2 mmol) in methanol (130 ml) under a nitrogen atmosphere, at room temperature. 2-ethoxy-4,5-dihydro-3H-pyrrole-3-carboxylic acid ethyl ester (3.4 g, 18.1 mmol) in methanol is added and the mire is stirred at 60° C. overnight. After cooling, the solvent is evaporated and the solid obtained is dissolved in water. The pH is adjusted at 5 with a 5 N HCl solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-ol 48 (1.88 g, 59%) is obtained as a white powder and used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([C:8](=[O:11])[CH2:9]Cl)[CH:7]=1.C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][CH2:9][C:8](=[O:11])[C:6]=2[CH:7]=1
Reactant: O=C(CCl)c1cc(Br)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1COc2ccc(Br)cc21
Yield: 30.1 %

Procedure:
A solution of 8.34 g (33.4 mmol) of 1-(5-bromo-2-hydroxyphenyl)-2-chloroethanone and 3.3 g (40.1 mmol) of anhydrous sodium acetate in 350 ml of methanol is heated at 65° C. for one hour, subsequently evaporated to dryness, the residue is taken up in 50 ml of water, and the aqueous mixture is extracted twice with 50 ml of methylene chloride each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (n-heptane/methylene chloride 7:3), giving 2.14 g of 5-bromobenzofuran-3-one as yellow solid; LC/MS: 214 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:13][C:14]([OH:15])=[N:16][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=CC(=O)c1ccc(Cl)cc1
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Oc1cnc(-c2ccc(Cl)cc2)cn1
Temperature: -30 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a stirred solution of (4-chloro-phenyl)-oxo-acetaldehyde (300 mg, 1.69 mmol) in methanol (15 mL) was added 2-amino-acetamide (187 mg, 1.69 mmol). The resulting mixture was cooled to −30° C. and 12.5M aqueous sodium hydroxide solution (0.3 mL) added. The resulting mixture was allowed to warm to −5° C. and was stirred at this temperature for 2 hours, followed by stirring at room temperature for 2 hours. Concentrated aqueous hydrogen chloride (0.3 mL) was added, followed by saturated sodium bicarbonate solution (1.0 mL). The reaction mixture was filtered and the resulting solid was washed with water (10 mL) and dried in a vacuum oven to afford the title compound as a brown solid (130 mg, 37%)
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].CCO.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.CCO>O>[C:14]1([C@@H:13]2[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)C1CS[C@H](c2ccccc2)N1
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
To the suspension of L-cysteine hydrochloride monohydrate (99.24 g, 565.1 mmol) in H2O (535 mL) were added EtOH (420 mL) and benzaldehyde (83.1 mL, 818 mmol) under stirring. After a few minutes, the mixture became a thick cream, which could not be stirred. Enough H2O/EtOH (3:2) solution was added to assist in stiffing the mixture. After 2.5 hrs, the mixture was filtered and the solid was washed with H2O and hexane successively. Upon drying under high vacuum, white powder (121.19 g) was obtained, which was used in the next step without further purification.
Reaction SMILES: C(O[C:6](=[O:13])[NH:7][C@H:8]([CH:11]=[O:12])[CH2:9][CH3:10])(C)(C)C.Br[C:15]([F:22])([F:21])C(OCC)=O.S([O-])(O)(=O)=O.[K+]>O1CCCC1.[Zn]>[CH2:9]([C@@H:8]1[NH:7][C:6](=[O:13])[C:15]([F:22])([F:21])[C@@H:11]1[OH:12])[CH3:10]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
tert-Butyl[(1S)-1-formylpropyl]carbamate (24.00 g) and ethyl bromodifluoroacetate (77.0 g) were dissolved in tetrahydrofuran (220 mL), and to a suspension of a zinc powder (25.4 g) in tetrahydrofuran (50 mL) was added dropwise the solution at room temperature. After heating under reflux for 1 hr, the mixture was cooled to room temperature, 1 mol/L aqueous potassium hydrogen sulfate solution (400 mL) was added, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→40%), the obtained oil was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (150 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (600 mL). Diisopropylethylamine (32.8 mL) was added, and the mixture was heated under reflux for 4 hr. The reaction solution was concentrated under reduced pressure, the residue was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/hexane to give the title compound as a white powder (yield: 7.20 g, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=O.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([C:21]2[C:22](=[O:23])[O:10][C:4]3[C:5]([CH:6]=2)=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=3)(=[O:19])=[O:20])=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]
Reactant: O=Cc1ccc(O)cc1O
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3ccc(O)cc3oc2=O)cc1[N+](=O)[O-]
Yield: 62 %

Procedure:
A solution of 4-hydroxysalicylaldehyde (1 mmol) and 2-(4-methoxy-3-nitrobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 62% yield of the title compound; m.p. 126-128° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:19])[C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1)c1ccccc1
Product: O=C(Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)c1ccccc1

Procedure:
Crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide (49 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 8.2 mg of 165. MS (Q1) 457 (M)+
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([F:30])[F:29])=[CH:24][CH:23]=2)[C:17]1=[O:31])(C(C)(C)C)(C)C>ClCCl>[F:30][CH:28]([F:29])[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([OH:15])[C:17]2=[O:31])=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1[C@@H](O)CCN1Cc1ccc(C(F)F)cc1
Reaction time: 2 h
Yield: 123 %

Procedure:
A solution of 4 M HCl in dioxane (0.62 mL, 2.5 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one (440 mg, 1.24 mmol) in dichloromethane (1.24 mL) at RT. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to afford (S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg, quantitative yield): LC-MS (M+H)+242.1.
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:29])=[CH:31][CH:32]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a mixture of 4-({cyclohexyl[5-(cyclohexylcarbonyl)-2-ethylthiophen-3-yl]methyl}amino)benzoic acid (130 mg) synthesized above, ethyl β-alaninate hydrochloride (66.2 mg), 1-hydroxybenzotriazole monohydrate (66.0 mg) and triethylamine (60 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82.6 mg), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (125 mg, 83%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][N:14]([CH:16]=O)[CH3:15].COS(OC)(=O)=O.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:13][N:14]([CH:16]=[C:3]1[C:4](=[O:12])[O:5][C:6]2=[CH:7][CH:8]=[CH:9][CH2:10][CH:11]2[C:2]1=[O:1])[CH3:15]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C=C1C(=O)OC2=CC=CCC2C1=O
Yield: 44.5 %

Procedure:
This compound was prepared by the method of example 2, by stirring 4-hydroxycoumarin (5.0 g) and DMF-dimethylsulfate (10.0 g) with ethyldiisopropylamine (10 mL) in CH2Cl2 (100 mL) for 0.5 hour. Product was crystallized from ether-CH2Cl2 to obtain 3.01 g of tan crystals, mp 135°-140° with decomposition.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1CC1NC(=O)NC1=O.[C:18]1([C:24]2(C3C=CC=CC=3)[NH:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH:23]=CC=C[CH:19]=1.C(N1C(=O)C(C)NC1=O)CCC.C(N1C(=O)C(CC2C=CC=CC=2)NC1=O)CCC.C(N1C(=O)CNC1=O)CCC>>[CH3:19][CH:18]([CH:24]1[NH:28][C:27](=[O:29])[NH:26][C:25]1=[O:30])[CH3:23]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: CCCCN1C(=O)CNC1=O
Agent: CCCCN1C(=O)NC(C)C1=O
Agent: CCCCN1C(=O)NC(Cc2ccccc2)C1=O
Product: CC(C)C1NC(=O)NC1=O

Procedure:
5-(1H-indol-2-ylmethyl)-2,4-imidazolidinedione; 5,5-diphenyl-2,4-imidazolidinedione; 3-butyl-5-methyl-2,4-imidazolidinedione; 3-butyl-5-(phenylmethyl)-2,4-imidazolidinedione; 3-butyl-2,4-imidazolidinedione,
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CCOC(=O)c1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A solution of 1-benzyl-4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (4) (1.2 g, 3.5 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (0.9 g, 10.5 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was evaporated and the residue was suspended in water, sonicated briefly, and extracted with dichloromethane. The combined organic phase was subsequently washed by water and brine, dried over Na2SO4, and evaporated to yield 1.12 g (82%) of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (5) as yellow solids. MP: 120° C.; 1H-NMR (DMSO-d6): δ 1.30 (t, J=6.9 Hz, 3H), 2.28 (m, 4H), 3.03 (m, 4H), 4.28 (q, J=6.9 Hz, 2H), 5.55 (s, 2H), 7.16-7.28 (m, 5H), 7.36 (m, 1H), 8.25 (dd, J=1.5, 7.5 Hz, 1H), 8.63 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 393 (M+1), 415 (M+23).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[NH:30]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:32]=[N:31]1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: O=C(Nc1nc2ccc(-c3cn[nH]c3)cn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 112 but starting from N-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide ((B5), 95 mg, 0.3 mmol, 1 eq.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (Boron-Mol, 85 mg, 0.36 mmol, 1.2 mol eq.) as a white solid (6.2 mg, 7%). HPLC, Rt: 2.26 min (purity: 99%). LC/MS M+(ESI): 305.2.