Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:29]([C:28]1[C:27]([Cl:26])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:36])=[O:30]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 92.8 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrirnidinyl)-L-phenylalanine methyl ester hydrochloride salt (3.12 mmol, 1.15 g) and 2,6-dichlorobenzoyl chloride (3.51 mmol, 0.735 g) in dichloromethane (40 mL) was added diisopropylethylamine (9.36 mmol, 1.63 mL) at room temperature. After 1 min, everything went into solution and the clear yellow solution was stirred for 20 h at room temperature. The resulting brown solution was diluted with dichloromethane (50 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 1.46 g (93% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C24H23Cl2N3O5 (M+H) 504.1093, found 504.1083.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.C(N(C(C)C)CC)(C)C>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:2]2[CH:7]=[N:6][C:5](=[O:8])[NH:4][C:3]=2[NH2:9])[CH2:11]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: Nc1nc(=O)[nH]cc1Br
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCCN(c2cnc(=O)[nH]c2N)C1

Procedure:
Method 8 was followed using 1 eq. of 5-bromocytosine, 1.05 eq. of tert-butyl piperidin-3-ylmethylcarbamate and 1.05 eq. of diisopropylethylamine yielding tert-butyl(1-(6-amino-2-oxo-1,2-dihydropyrimidin-5-yl)piperidin-3-yl)methylcarbamate as an orange crunchy solid (18%). LCMS (m/z): 324.1 (MH+); LC Rt=1.90 min.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](CC3C=CC=CC=3)[CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Yield: 95.5 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (13.0 g, 32.6 mmol) and 10% palladium on carbon (50% water, 3.6 g) in glacial acetic acid (160 ml) was treated with hydrogen gas (50 psi) on a Parr shaker for 16 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-methylxanthine (9.6 g, 96% yield) as a white colored solid.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49]>>[C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:46][C@H:47]([C:51]([OH:53])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:30])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 88.4 %

Procedure:
Starting from 5-(3-hexadecanoyloxyoctadecanoyl)aminovaleric acid (1.27 g) and L-threonine (950 mg), N-[5-(3-hexadecanoyloxyoctadecanoyl)aminovaleryl]-L-threonine (1.3 g) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=O)=[O:7])([CH3:4])[CH3:3].[BH3-]C#[N:19].[Na+]>CO>[NH2:19][CH:14]1[CH2:16][CH:9]2[N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH:12]([CH2:11][CH2:10]2)[CH2:13]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(N)C2
Yield: 98.9 %

Procedure:
A stirred mixture of Boc-nortropinone (287 mg, 1.3 mmol), NH4OAc (1.96 g, 25.5 mmol), NaCNBH3 (800 mg, 12.7 mmol) and MeOH (20 mL) was heated at reflux for 2 h. The mixture was concentrated, the residue was diluted with 0.5 M aq NaOH (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated to afford tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (291 mg, quant) as a mixture of isomers. LC-MS Method 1 tR=0.88 min, m/z=227.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:21])[C:5](=[O:20])[C:6]=1[Sn](CCCC)(CCCC)CCCC.I[C:23]1[CH:24]=[C:25]([NH:29][C:30]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[NH:37][CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[O:31])[CH:26]=[CH:27][CH:28]=1.CCOC(C)=O>[Cu](I)I.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:21])[C:5](=[O:20])[C:6]=1[C:27]1[CH:26]=[C:25]([NH:29][C:30]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[NH:37][CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)=[O:31])[CH:24]=[CH:23][CH:28]=1
Reactant: O=C(Nc1cccc(I)c1)c1sccc1NCc1ccnc2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC)c(=O)c1=O
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(-c2cccc(NC(=O)c3sccc3NCc3ccnc4ccccc34)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitrogen was bubbled through a solution containing 3-methoxy-4-tributylstannanylcyclobut-3-ene-1,2-dione (0.40 g, 1.0 mmol) and 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylic acid (3-iodophenyl)amide (0.54 g, 1.1 mmol) for 5 min, then benzylchlorobis(triphenyl phosphine)Pd(II) (45 mg, 0.06 mmol) and copper iodide (17 mg, 0.09 mmol) were added. The mixture stirred at rt for 1 h. EtOAc (50 mL) was added and the mixture was filtered, partitioned over saturated aqueous NH4Cl, and then washed with 10% aqueous KF solution. The aqueous layer was back-extracted with EtOAc (3×50 mL) and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The mixture purified by silica gel chromatography (100% EtOAc) to yield a yellow oil. CH2Cl2 was added and the solution was sonicated. Title compound 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylic acid [3-(2-methoxy-3,4-dioxocyclobut-1-enyl)phenyl]amide precipitated out as a yellow solid and was filtered. MS (ES): m/z 470.0 [M+1]. 1H NMR (DMSO-d6, 400 MHz): δ=4.54 (s, 3H), 5.10 (d, J=6.4 Hz, 2H), 6.80 (d, J=3.2 Hz, 1H), 7.40 (d, J=4.0 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.60-7.64 (m, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 8.06 (d, J=8.08-8.12 (m, 1H), 8.32 (s, 1H), 8.85 (d, J=4.0 Hz, 1H), 9.75 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[NH2:7].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15]>>[CH3:12][O:11][C:9]1[CH:10]=[C:4]([O:3][CH3:2])[CH:5]=[C:6]2[C:8]=1[C:13](=[O:17])[C:14](=[O:15])[NH:7]2
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Product: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Yield: 99.6 %

Procedure:
12 g (63 mmol) of 3,5-dimethoxyaniline hydrochloride and 20 ml (230 mol) of oxalyl chloride were stirred at 165° C. for 30 min. The excess of oxalyl chloride was distilled (the color of the reaction mixture changed from dark-red to green-yellow). The reaction mixture was cooled and methanol was added. The resulting suspension was heated then filtered, washed with methanol and dried to yield 13 g of 4,6-dimethoxyindole-2,3-dione (100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1.CN(C)C=O.[Br:33]Br>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([Br:33])[C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1
Reactant: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br)c1cccc([N+](=O)[O-])c1
Yield: 96.6 %

Procedure:
428 g (1.0 mol) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-5-oxo-2-pyrazoline was added to 2.2 liters of dimethylformamide. To the solution, there was added dropwise 160 g (1.0 mol) of bromine with stirring while cooling with ice, and after stirring for about 1 hour, the reaction solution was poured into 9 liters of water. The crystals thus-separated were collected by filtration to obtain 489.5 g (96.6% yield) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-4-bromo-5-oxo-2-pyrazoline.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([OH:16])[CH:9]=1)[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:18]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([OH:16])[CH:9]=2)=[CH:21][CH:20]=1)#[N:17]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1ccc(OC)c(O)c1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC)c(O)c1

Procedure:
(RS)-Ethoxy-(3-hydroxy-4-methoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(3-hydroxy-4-methoxy-phenyl)-acetamide. Light yellow gum.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2].[CH2:10](O)[CH2:11][CH2:12][CH3:13].O>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][CH2:8][OH:9])(=[O:4])[O:5][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCP(=O)(O)CCCO
Reactant: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOP(=O)(CC)CCCO
Yield: 83.9 %

Procedure:
456 g (3 mol) of ethyl-3-hydroxypropylphosphinic acid (produced as in Example 10) are at 85° C. dissolved in 400 ml of toluene and admixed with 888 g (12 mol) of butanol. At a reaction temperature of about 100° C., the water formed is removed by azeotropic distillation to obtain 524 g (84% of theory) of butyl ethyl(3-hydroxy-propyl)phosphinate purified by distillation at reduced pressure.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10]O)[C:4]=1[OH:12].[H][H]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[OH:12]
Reactant: [H][H]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Solvent: CO
Product: Cc1cc(C)c(O)c(C)c1

Procedure:
108 g of o-cresol, 215 g of 38 wt% formalin, 50 g of sodium hydroxide, and 200 g of water were reacted for 96 hours at 25° C., and the reaction mixture was then neutralized with acetic acid, to obtain 126 g of 2,6-bis(hydroxymethyl)-4-methylphenol. (Yield: 75 mol%) The obtained 2,6-bis(hydroxymethyl)-4-methylphenol was reacted in 250 ml of methanol in the presence of 0.375 wt% of platinum-alumina catalyst and hydrogen for 4 hours at 180° C. at 179 kg/cm2 -G, and 15 g of 2,4,6-trimethylphenol was obtained. (Yield: 45 mol%) The yield on the basis of the raw material was 34 mol%.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)=[CH2:2].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C1(C)C=CC=CC=1>[N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=[CH:12][C:3]=1[CH:1]1[CH2:2][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=Cc1ccc2c(n1)CCCC2
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1ccc2c(n1)CCCC2

Procedure:
A solution of 2 (1.6 g, 10 mmol) in toluene (50 ml) was treated with ethyl diazoacetate (1.7 g, 15 mmol) and stirred at reflux overnight. The mixture was concentrated and the residue was purified by gradient elution on silica gel (0 to 10% EtOAc in hexanes) to afford the title compound as a pale yellow oil. LRMS m/z (M+H) 246.2 found, 246.2 required.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-])=O.Cl.[H][H]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](NC(=O)Cc3ccc([N+](=O)[O-])cc3)[C@H]2SC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](NC(=O)Cc3ccc(N)cc3)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
The catalyst was added to a solution of 406 mg of DL cis 7-p-nitrophenylacetamido-3-isopropyl-3-cepheme-4-carboxylic acid in 3.8 ml of dimethylformamide and 1.12 ml of N hydrochloric acid and a current of hydrogen was passed therethrough until saturated. The mixture was filtered and the filter was washed with a 50--50 water-ethanol solution containing a few drops of hydrochloric acid. The filtrate was evaporated to dryness and the residue was taken up in 3 ml of water. Ammonium formate was added thereto to a pH of 4.5 and the mixture was stirred 5 minutes and vacuum filtered. The precipitate was empasted with water and dried to obtain DL cis 7-p-aminophenylacetamido-3-isopropyl-3-cepheme-4-carboxylic acid melting at 150° C with decomposition. The product occurred as ocre crystals slightly soluble in water, ethanol and chloroform and insoluble in ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a light brown solid (207 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][CH2:16][C:17]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:27]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][C:17]1[C:25]2[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=2[NH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2c[nH]c3c2C(=O)CCC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2[nH]cc(CCC(=O)N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-(4-Oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionyl]-piperazine-1-carboxylic acid tert-butyl ester (37.5mg, 0.1 mmol) was added to 3 ml of dichloromethane at 0° C. followed by the addition of 1 ml of 20% trifluoroacetic acid. The reaction mixture was stirred at room temperature for 8 hours. The reaction solution was rotary evaporated and diluted with 1,4-dioxane. The reaction solution was concentrated at 30° C. till dryness then purified by flash chromatography and eluting with (chloroform: methanol: ammonia 20/1/0.1, 15/1/0.1) to provide 3-(3-oxo-3-piperazin-1-yl-propyl)-1,5,6,7-tetrahydro-indol-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1.[N+:11]([O-])([OH:13])=[O:12]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C)[n+]([O-])c1
Solvent: CC(=O)O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 6 h

Procedure:
5-methoxy-2-methylpyridine-1-oxide (6 g, 43.1 mmol) and nitric acid (18.4 mL, 431 mmol, 1.48 g/mL) was added to AcOH (50 mL) and the reaction was stirred at 90° C. for 6 h. The mixture was concentrated (1/4) and neutralized at 0° C. was addition of ammonium hydroxide. The mixture was extracted with EtOAc, washed with brine and water, dried (Na2SO4), filtered and concentrated. The product crystallised during concentration. tR: 0.50 min (LC-MS 2); ESI-MS: 185.1 [M+H]+ (LC-MS 2).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.B([O-])([O-])O[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+].COCCOC>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.O>[N:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: [O-]B([O-])Oc1ccncc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 3 h
Yield: 56.3 %

Procedure:
To a mixture of ethyl 4-bromobenzoate (2.29 g), 4-pyridyl borate (1.23 g), 1 M sodium hydrogen carbonate solution (30 ml) and 1,2-dimethoxyethane (40 ml) was added tetrakis(triphenylphosphine)palladium (0.3 g) and the mixture was stirred for 3 hours with reflux under nitrogen atmosphere. To the mixture was added water and the solution was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography, and eluted with hexane-ethyl acetate (2:1) to give the title compound as crystals (1.15 g, 50.7%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[CH:11][C:12](OCC)=[O:13])=[CH:8][N:7]=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=1)[CH3:2].N12CCCN=C1CCCCC2>C(N(CC)CC)C>[CH2:1]([N:3]1[C:4]2[N:5]=[C:6]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:7]=[CH:8][C:9]=2[CH:10]=[CH:11][C:12]1=[O:13])[CH3:2]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)ccc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of ethyl 3-(4-ethylamino-2-phenylamino pyrimidin-5-yl)acrylate (179 mg, 0.57mmol) in 10 mL of triethylamine was added 90 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture was heated at reflux for 8.5 hours then stirred at room temperature overnight. An additional amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (90 μL) was added, and the reaction mixture was heated at reflux for 9 hours then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by flash chromatography, followed by recrystallization from ethyl acetate:hexane, to provide 8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp 203-204° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[BrH:16].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:16][CH2:3][CH2:2][CH2:1][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)=[O:5]
Reactant: Br
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(CCCBr)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
20 g (88.6 mmol) of 4-chloro-3-nitrophenyl cyclopropyl ketone is added to a solution of 65 m of 32% HBr/acetic acid in 300 ml acetic acid and heated to 80° C. for 5 hr. The reaction mixture is cooled to room temperature and poured nto 1 L of 10% potassium carbonate solution, dried over MgSO4 filtered and treated with charcoal. The solvent is removed in vacuo, and the residue is crystallized from ether to provide the title compound.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[I:16]CI.N(OCCC(C)C)=O>C1COCC1.[Cu]I>[I:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: ICI
Reactant: COC(=O)c1ccc(N)cc1C(F)(F)F
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)cc1C(F)(F)F
Temperature: 25 °C
Yield: 74.5 %

Procedure:
Methyl 4-amino-2-(trifluoromethyl)benzoate (˜22 mmol), was dissolved in THF (100 mL) and the mixture was sparged with nitrogen for 15 minutes. Copper (I) iodide (4.14 g, 21.8 mmol) and diiodomethane (8.8 mL, 109 mmol) were added followed by isoamyl nitrite (8.8 mL, 66.2 mmol) and the mixture was stirred at reflux for 4 h. The mixture was cooled to ambient temperature and then was partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous portion was extracted with ethyl acetate (2×). The combined organic portion was washed sequentially with 1:1 saturated sodium bicarbonate solution: 1 M sodium thiosulfate (2×) and brine, dried over sodium sulfate, then filtered and concentrated to provide a brown oil which was purified by column chromatography (silica gel, 2-40% dichloromethane in hexanes) to afford methyl 4-iodo-2-(trifluoromethyl)benzoate (5.42 g, 16.4 mmol, ˜75% yield over 2 steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.97 (dd, 1H), 7.52 (d, 1H), 3.93 (s, 3H); GCMS for C9H6F3IO2: 330 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B.CO>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(CBr)cc1Br
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
The compound of Step 1 (23.8 g, 81 mmol, 1 eq) was dissolved in THF under nitrogen at 0° C. A 1M borane solution in THF (242 ml, 242 mmol, 3 eq) was then added dropwise and the mixture was stirred at RT for 1 hour under nitrogen. The solution was cooled in an ice bath and 125 ml of methanol was then added slowly. The solvent was removed and the mixture partitioned between 400 ml of water and 400 ml of 20% THF/EtOAc. The aqueous layer was washed 3 times with 400 ml of 20% THF/EtOAc and the combined organic layers were dried with sodium sulfate. The solvent was removed and 19.7 g (87%) of the title compound was obtained.