Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:19])[CH2:63][CH2:62]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Cl)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (2 mL) was added, DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.081 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.082 g (77%) of 3-[4-(2-chloro-phenylamino)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 449.17 (M+1)+, 98.46%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (s, 1H), 8.2 (dd, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.5-7.2 (m, 2H), 7.3 (d, 1H), 7.2 (t, 1H), 6.9 (d, 1H), 6.4 (t, 1H), 4.9 (d, 1H), 4.4 (d, 1H), 4.0 (d, 1H), 3.7-3.6 (m, 3H), 3.3-3.2 (m, 1H), 2.9-2.7 (m, 1H), 2.0 (t, 2H), 1.6-1.5 (m, 1H), 1.4-1.3 (m, 1H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:25])[CH2:6][C:7]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][C:15]2[CH:20]=[C:19]([Br:21])[C:18]([OH:22])=[C:17]([Br:23])[CH:16]=2)=[C:9]([Br:24])[CH:8]=1.Cl>O1CCCC1>[Br:13][C:11]1[CH:12]=[C:7]([CH2:6][C:5]([OH:25])=[O:4])[CH:8]=[C:9]([Br:24])[C:10]=1[O:14][C:15]1[CH:16]=[C:17]([Br:23])[C:18]([OH:22])=[C:19]([Br:21])[CH:20]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(Br)c(O)c(Br)c2)c(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Br)c(Oc2cc(Br)c(O)c(Br)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of methyl[3,5-dibromo-4-(3-formyl-4-hydroxy-5-methyl-phenoxy)phenyl]acetate (60 mg, 0.13 mmol) and trifluoroacetic acid (1.5 mL), triethylsilane (62 μl, 0.39 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours, the organic phase concentrated and the residue was co-evaporated (toluene) to give 60 mg of crude methyl[3,5-dibromo-4-(3,5-dibromo-4-hydroxyphenoxy)phenyl]acetate. The crude product was used in next step. Lithium hydroxide (1.5 ml, 1N) was added to a stirred solution of crude methyl[3,5-dibromo-4-(3,5-dibromo-4-hydroxyphenoxy)phenyl]acetate and tetrahydrofuran (1.5 mL). The resulting mixture was stirred for 2 hours at room temperature, acidified with hydrochloric acid (1 N) and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified on column (HPLC, C8, gradient eluent: acetonitrile/water (0.5% formic acid) from 1:4 to 1:0) to give 16 mg (14% for both steps) of 3,5-dibromo-4-(3,5-dibromo-4-hydroxyphenoxy)phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])O
Reactant: COc1c(C)cccc1C
Product: COc1c(C)cc([N+](=O)[O-])cc1C
Reaction time: 18 h
Yield: 62 %

Procedure:
2,6-Dimethylanisole (2, 36 g, 260 mmol) was added dropwise over 0.5 h to stirred cold cone. nitric acid (200 mL) contained in round-bottom flask; stirring at room temperature was continued for 18 h. The mixture was poured onto crushed ice contained in a 1-L beaker. The resulting bright yellow solid was vacuum-filtered and dried. Recrystallization from ethanol-water gave 2,6-dimethyl-4-nitroanisole (3, 29 g, 62% yield) as a pale yellow solid, mp 90°-91° C. (lit.: Burton, G. W.; Joyce, A.; Ingold, K. U. Arch. Biochem. Biophys., 1982, 221, 281; 89°-91° C.).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:31])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[N:17])[CH:12]=3)[C:7]=2[C:6](=[O:18])[C:5]2[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:22][C:4]1=2.[O:32]1[CH2:35][C:34](=O)[CH2:33]1.C1COCC1.C([BH3-])#N.[Na+]>C(O)(=O)C.O.CO>[CH3:2][C:3]1([CH3:31])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[N:17])[CH:12]=3)[C:7]=2[C:6](=[O:18])[C:5]2[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([CH:34]4[CH2:35][O:32][CH2:33]4)[CH2:27][CH2:26]3)=[CH:22][C:4]1=2
Reactant: O=C1COC1
Reactant: CC1(C)c2cc(OCC3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC1(C)c2cc(OCC3CCN(C4COC4)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reaction time: 8 h
Yield: 43.9 %

Procedure:
6,6-Dimethyl-11-oxo-8-(piperidin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloric acid salt (Compound A7-25, 30 mg, 0.075 mmol) and oxetan-3-one (38 mg, 7 eq.) were dissolved in acetic acid (0.2 ml), THF (1 ml) and methanol (1 ml), added with sodium cyanoborohydride (33 mg, 7 eq.) at room temperature, and stirred overnight. The reaction solution was added with water, and then extracted with ethyl acetate. The solution was dried over sodium sulfate and the solvent was removed under vacuum and the resulting residues were purified by preparative TLC (chloroform: 2 N ammonia methanol=9:1) to obtain the target compound (15 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CS(Cl)(=O)=O.CCN(CC)CC.O>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Fc1cccc(-c2cc3ccc(C(F)(F)F)cn3n2)c1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 84.2 %

Procedure:
To a suspension of 1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (10.0 g, 33.53 mmol) in DME (38 ml) was added MsCl (2.6 ml, 33.53 mmol) at 0° C. The suspension was stirred for 15-20 min and then Et3N (9.3 ml, 67.1 mmol) dissolved in DME (4 ml) was added dropwise at a rate to maintain the temperature ≦5° C. After the addition was complete, the suspension was warmed to room temperature and stirred for 1 hour. Additional Et3N (0.47 ml, 3.35 mmol) was added and the solution was stirred for 15 min at 30-35° C. The suspension was cooled to room temperature and filtered to remove the salts. The cake was washed with twice with DME (10 ml) and the filtrate was transferred to a clean reaction flask. To the filtrate was added FeCl2 (42 mg, 0.34 mmol) at room temperature. The solution was heated to 70° C. and stirred for 30 min. After cooling the solution to 40° C., H2O was added (80 ml). The resultant suspension was cooled to 0-5° C. and stirred for 30 min. The solid was isolated by filtration and partially dried via airflow. The solid was further dried under reduced pressure (20 in Hg Vacuum) at 50° C. to afford 7.91 g (84%) of the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[CH2:23]([N:25]([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:12][S:11][C:10]=2[CH:13]=1)[CH2:26][CH2:27][OH:28])[CH3:24]
Reactant: CCNCCO
Reactant: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1
Product: CCN(CCO)CCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 19.1, 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and 2-(Ethylamino)ethanol were converted to yield 2-(Ethyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amino)-ethanol as light brown oil, MS: 382 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:5][C:3]=1[NH2:4].[N:16]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:5][C:3]=1[NH:4][NH2:16]
Reactant: Cc1cc(Cl)c(N)cc1SCC(F)(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Cl)c(NN)cc1SCC(F)(F)F
Reaction time: 1 h
Yield: 84.7 %

Procedure:
13.5 g of 2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)aniline was added dropwise to 30 ml of concentrated hydrochloric acid at room temperature, and to this mixture, an aqueous solution containing 3.8 g of sodium nitrite was added dropwise at from 0 to 5° C., and the mixture was stirred as it was for 1 hour to prepare a diazonium salt. 36 g of tin chloride dihydrate was dissolved in 250 ml of 6N hydrochloric acid, and to this mixed solution, the above aqueous diazonium salt solution was added dropwise at from 0 to 5° C., and the solution was further stirred at room temperature for 2 hours. Toluene was added, the solution was neutralized with an aqueous sodium hydroxide solution, the insolubles were filtered off, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 12.1 g of 2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[C:9]([C:11]3[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=3[CH2:19][C:4]=2[CH:3]=1)=[O:10]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[C:9](=[O:10])[C:11]3[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[C:13]4[C:12]=3[C:19](=[C:19]3[C:12]5=[C:13]4[C:14]([OH:18])=[CH:15][C:16]([OH:17])=[C:11]5[C:9](=[O:10])[C:5]4[C:6]([OH:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]3=4)[C:4]=2[CH:3]=1
Reactant: Cc1cc(O)c2c(c1)Cc1cc(O)cc(O)c1C2=O
Solvent: CCO
Product: Cc1cc(O)c2c(=O)c3c(O)cc(O)c4c5c(O)cc(O)c6c(=O)c7c(O)cc(C)cc7c(c65)c(c2c1)c34

Procedure:
Emodin anthrone is dimerized to give the 10,10′-coupled bianthrones by reacting emodin anthrone with ferric chloride (FeCl3) in ethanol, as described in Kinget, R., Planta. Med., vol. 15, pp. 233-39 (1967), which is also incorporated herein by specific reference. This reaction results in two diastereomers, the meso and the dl-pair. These compounds are readily separated on reverse phase high pressure liquid chromatography (“HPLC”). Subsequent oxidation of the bianthrones with oxygen in methanol containing triethylamine produces protohypericin, which is converted into hypericin upon exposure to sunlight. Alternatively air oxidation of the bianthrones in hot ammonium hydroxide and exposure to sunlight give rise to hypericin. The resulting compounds are characterized by HPLC, thin layer chromatography (“TLC”), and ultraviolet/visual spectrometry.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:15][C@@H:14]3[CH2:16][CH2:17][C@H:10]2[CH2:11][NH:12][C:13]3=O)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.Cl[C:33]1[N:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([F:43])[CH:39]=2)[N:34]=1>C1COCC1.CC(N(C)C)=O>[F:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([N:12]1[CH2:11][C@@H:10]3[CH2:17][CH2:16][C@@H:14]([CH2:15][N:9]3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13]1)[N:42]=[CH:41]2
Reactant: COc1ccc(N2C[C@@H]3CC[C@H]2CNC3=O)cc1
Reactant: Fc1ccc2nc(Cl)ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1ccc(N2C[C@@H]3CC[C@H]2CN(c2ncc4cc(F)ccc4n2)C3)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]-nonan-2-one (E-4, 0.108 g, 0.438 mmol, 1.0 equiv) in THF (3.0 mL) at ambient temperature was added a solution of lithium aluminum hydride in THF (1.31 mL, 1.31 mmol, 1.0M, 3.0 equiv) and the reaction mixture was heated to 65° C. for 2 h. The reaction was cooled to 0° C. and quenched with water (0.1 mL), 1M NaOH (0.2 mL), and water (0.3 mL). The reaction mixture was stirred a further 0.5 h, diluted with ethyl acetate (50 mL), dried over MgSO4, and concentrated to an oil. To a solution of the residual oil in dimethylacetamide (2.1 mL) was added triethylamine (0.24 mL, 1.72 mmol, ca. 4 equiv), and 2-chloro-6-fluoroquinazoline (0.094 g, 0.52 mmol, ca. 1.2 equiv) and the reaction was heated to 175° C. for 15 minutes in the microwave. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was dried over MgSO4 and concentrated. The residue was purified by column chromatography (0 to 60% ethyl acetate in hexanes) to afford E-5 as a yellow solid. ESI MS [M+H] for C22H23FN4O=379.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.ClC1C=CC(NN=C2CCCC(=O)C2)=CC=1>O.FC(F)(F)C(O)=O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]2=1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C1CCCC(=NNc2ccc(Cl)cc2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
A suspension of p-chlorophenylhydrazine hydrochloride (8.06 g, 45 mmol) in water is added over a 10 min. period to a solution of 1,3-cyclohexanedione (5.05 g, 45 mmol) in water, stirred for 16 h and filtered. The filtercake is washed with water and air-dried. The thus-obtained cyclohexane-1,3-dione mono-(4-chlorophenyl)-hydrazone (45 mmol th.) is dissolved in trifluoroacetic acid (TFA) (30 mL), heated at 80° C. for 16 h, cooled to room temperature, poured into ice-water and filtered. The filtercake is air-dried and recrystallized from ethanol/water to afford the title product as a tan solid, 4.2 g (42% yield) identified by NMR and mass spectral analyses.
Reaction SMILES: [H-].[Na+].[CH2:3]1[N:14]2[C:15]3[CH:7]([CH2:8][CH2:9][C:10](=[O:16])[C:11]=3[CH:12]=[CH:13]2)[CH2:6][NH:5][CH2:4]1.I[CH3:18]>CN(C)C=O>[CH3:18][CH:9]1[CH2:8][CH:7]2[CH2:6][NH:5][CH2:4][CH2:3][N:14]3[C:15]2=[C:11]([CH:12]=[CH:13]3)[C:10]1=[O:16]
Reactant: O=C1CCC2CNCCn3ccc1c32
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC2CNCCn3ccc(c32)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 731.3 %

Procedure:
Add sodium hydride (0.78 g, 1.9 mmol, 60% in mineral oil) to 1,2,4,5-tetrahydro-6H-[1,4]diazepino[6,7,1-hi]indol-7-one (3.05 g, 1.62 mmol) in dry dimethylformamide (77 mL). Stir for 30 minutes at room temperature and then add iodomethane (2.0 mL, 3.2 mmol). Stir at room temperature for 134 minutes. Partition between ethyl acetate (1 L) and water (500 mL). Wash the organic phase with saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to chromatography (pre-packed silica gel), eluting with a gradient: 1:0-9:1 ethyl acetate/methanol to provide the desired compound (2.42 g, 74%) as an off-white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[N:15]=[CH:14]1.O>S(=O)(=O)(O)O>[F:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[N:15]=[CH:14]1
Reactant: O=[N+]([O-])O
Reactant: Cc1c(C(F)(F)F)ncn(-c2ccc(F)cc2F)c1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)ncn(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Yield: 73.9 %

Procedure:
Fuming nitric acid (1.63 g) was added to a solution of 3-(2,4-difluorophenyl)-5-methyl-6-trifluoromethylpyrimidin-4-one (7.5 g) in conc. sulfuric acid (50 g) at 10° C. The reaction mixture was poured into water, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 3-(2,4-difluoro-5-nitrophenyl)-5-methyl-6-trifluoromethylpyrimidine-4-one (6.4 g), m.p. 156.7° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)cc(O)c1
Product: CC(=O)Oc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
206.5 g (1.69 mol) of 3,5-dimethylphenol and 337.3 g (3.30 mol) of acetic anhydride were refluxed for 1 h and then stirred at RT overnight. The mixture was poured onto water and extracted with methylene chloride. The organic phase was washed with sodium hydroxide solution and water, dried and concentrated under reduced pres-sure. 286 g of 3,5-dimethylphenyl acetate were obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[CH2:3][CH2:2]1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[NH:11])[O:12][CH2:13][CH3:14])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC[O-]
Reactant: N#Cc1cc(C2CC2)ccn1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)c1cc(C2CC2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of 4-cyclopropylpicolinonitrile (0.04 g, 0.27 mmol) in ethanol was added sodium ethoxide (0.022 g, 0.33 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum, quenched with water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 4-cyclopropylpicolinimidate (0.045 g). The material was used without further purification. MS (ES+APCI) (M+H) 190.9; LCMS retention time 1.700 min (Method G).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[C:11]4[C:16]([CH:17]=[CH:18][CH:19]=3)=[CH:15][N:14]=[CH:13][C:12]=4[C:7]=2[CH:6]=[CH:5][C:4]=1[O:20][CH3:21].Cl>[Pt](=O)=O.C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[C:11]4[CH:12]([CH2:13][NH:14][CH2:15][C:16]=4[CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:20][CH3:21]
Reactant: COc1ccc2c(c1OC)Oc1cccc3cncc-2c13
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1OC)Oc1cccc3c1C2CNC3
Reaction time: 24 h

Procedure:
Platinum (IV) oxide (200 mg) was added to a solution containing 50 ml of acetic acid and isoquinoline 6 (1 g; 3.5 mmol). After adding 2.8 ml of concentrated HCl, the mixture was shaken on a Parr hydrogenator at 60 psi for 24 hours. The green solution was filtered through Celite to remove the catalyst and the majority of the acetic acid was removed by rotary evaporation. The remaining acid was neutralized using a saturated sodium bicarbonate solution, extracted with diethyl ether (3×250 ml), dried (Na2SO4), and concentrated. The resulting oil (0.997 g; 99%) was used without further purification: 1H NMR: (300 MHz, CDCl3): 7.10 (t, 1H, J=7.5 Hz); 7.00 (d, 1H, J=8.4 Hz); 6.78 (m, 2H); 6.60 (d, 1H, J=9 Hz); 4.10 (s, 2H); 3.84 (m, 8H); 2.93 (t, 1H, J=12.9 Hz).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH:27]([NH:29][CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1)=[O:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:37]3[CH:36]=[C:33]4[S:34][CH:35]=[C:31]([CH2:30][NH:29][CH:27]=[O:28])[N+:32]4=[CH:38]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: O=CNCc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CNC=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 1.2 %

Procedure:
The same procedure as in Example 1 was repeated except that 88 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-(formylamino)methylimidazo[5,1-b]thiazole were used, thereby obtaining 1.2 mg of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20]([C:38](=[O:46])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:20]([C:38]([NH:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:46])=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2C(=O)Nc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cc(NCC3CCNCC3)c(C(=O)Nc3ccccc3)cn2)cn1
Reaction time: 0.33 h
Yield: 65.3 %

Procedure:
TFA (0.05 mL) was added to a solution of tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (11.0 mg, 0.02 mmol) in dichloromethane (0.5 mL) at room temperature. After 20 minutes, solvent was evaporated and the crude product was purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated to give 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-4-ylmethylamino)nicotinamide as a yellow solid (5.6 mg, 63%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[N:13]([CH3:20])[C:12]3[C:7]2=[N:8][C:9]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=2[O:31][CH3:32])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:33]1([CH:38]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([N:6]2[CH2:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]3[C:7]2=[N:8][C:9]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:44][CH:41]4[CH2:40][CH2:39][CH:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:43][CH2:42]4)=[O:28])=[CH:24][C:23]=2[O:31][CH3:32])=[N:10][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: NC1CCC(N2CCCC2)CC1
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: CN(C)C=O
Product: COc1cc(C(=O)NC2CCC(N3CCCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C

Procedure:
To a solution of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Intermediate 236; 83 mg, 0.19 mmol) in DMF (3 mL) was added a solution of 4-pyrrolidin-1-ylcyclohexan-1-amine (Intermediate 237; 78 mg, 0.46 mmol). DIPEA (100 uL, 0.57 mmol) was added, followed by HATU (107 mg, 0.28 mmol). The resultant mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated to a gum, which was partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic phase was separated by gravity elution through a PTFE filter cup and evaporated to an amber gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as an off white solid (34 mg, 30%).