Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (92%). m.p. 95-98° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.74, 7.65-7.52, 7.35, 6.99, 4.08-3.22, 1.55-1.46, 0.80-0.67, 0.48-0.42, 0.10-0.07. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.4, 134.2, 132.3, 129.5, 127.2, 127.1, 126.9, 121.8, 118.2, 112.5, 46.3, 44.5, 44.4, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH:7]=[CH:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[O:6][CH:5]2[CH:7]=[CH:8][C:9](=[O:10])[CH:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@@H](O)C=C[C@H]2O1
Solvent: ClCCl
Product: CC1(C)OC2C=CC(=O)C2O1
Reaction time: 72 h

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-1) (3 g, 19.2 mmol, 1 equiv) was dissolved in DCM (96 mL) and PS-IBX (32 g, 1.2 mmol/g loading, 2 equiv) was added. The mixture was rotated for 3 days at ambient temperature. Upon disappearance of starting material, the resin was filtered off washing with DCM (3×50 mL). The filtrate was concentrated to afford 3aR,6aR)-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (5-1) as a tan solid. 1H NMR (500 MHz, CDCl3): δ 7.61 (dd, J=5.5, 2.5 Hz, 1H); 6.21 (d, J=6.0 Hz, 1H); 5.27 (dd, J=5.5, 2.5 Hz, 1H); 4.46 (d, J=5.5 Hz, 1H); 1.41 (d, J=3.0 Hz, 6H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=3[N:4]([CH3:20])[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1ccc2c(c1)N(C)C(=O)C(N)N=C2c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccc(C)cc3N(C)C2=O)c1
Reaction time: 0.33 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1,8-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 3-methoxyphenylisocyanate, and triethylamine were mixed in THF at 0° C. and stirred 20 minutes. Removal of THF in vacuo and crystallization from MeOH gave the title compound: m.p. 184°-188° C.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC>C([O-])(O)=O.[Na+]>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[S:8][CH:9]=1
Reactant: CC(=O)c1nc(CCl)cs1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2nc(CCl)cs2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (992 mg, 5.65 mmol) in ethylene glycol (6.30 mL, 112.96 mmol) was treated with trimethylorthoformate (1.24 mL, 11.30 mmol) followed by LiBF4 (106 mg, 1.13 mmol). The reaction mixture was heated at 95° C. for 2 h. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil: TLC:rf (4:1 hept-EA)=0.30. LC-MS-conditions 02: tR=0.84 min, [M+H]+=220.36.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][C@H:18]([NH:17][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=2)[CH2:27][CH2:26]3)[CH2:29][CH2:30]1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(Oc4ccccc4)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Phenoxybenzoic acid (1.0 g, 4.7 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (99 mg, 0.42 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (99 mg, 0.41 mmol) and triethylamine (83 μL, 0.42 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 120 mg (68%) of the title compound as an oil. The oil crystallized from diethyl ether/hexane: mp 136-137° C.; [α]21D −9.0° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 441 (31, M+).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH:17]=[CH:18][C:19]2[S:23][C:22]3=[CH:24][N:25]=[CH:26][N:21]3[CH:20]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8].C(OCC)(=O)C>CN(C=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH:17]=[CH:18][C:19]2[S:23][C:22]3=[CH:24][N:25]=[CH:26][N:21]3[CH:20]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=Cc1cn2cncc2s1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C=Cc1cn2cncc2s1
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
Potassium thioacetate (0.22 g) is added to a solution of 1.07 g of (3R,5S)-1-allyloxycarbonyl-3-methane sulfonyloxy-5-[2-(imidazo[5,1-b]thiazol-2-yl)vinyl]pyrrolidine (a mixture of geometrical isomers) in 5 ml of DMF, and the mixture is stirred at 70° C. for 4 hr. Ethyl acetate is added to the reaction mixture, and the mixture is successively washed with water and a saturated aqueous sodium hydrogencarbonate solution, and saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation. The residue is purified by column chromatography on silica gel to give 0.42 g of the title compound.
Reaction SMILES: BrC1C(OC)=C(C=CC=1CSC1C=CC=CC=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:44][CH3:45])=[C:27]([C:33]([CH2:36][S:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29].[Cl:46]C1C=C(S)C=CC=1>>[Br:24][C:25]1[C:26]([O:44][CH3:45])=[C:27]([C:33]([CH2:36][S:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:46])[CH:39]=2)=[CH:34][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: Sc1cccc(Cl)c1
Agent: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Product: CCOC(=O)c1c(CSc2cccc(Cl)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87) and 3-chlorothiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([O:19]C)=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([OH:19])=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2
Reactant: COC(=O)CN1CCSC(c2ccc(Cl)cc2Cl)c2c(-c3ccccn3)nn(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2ccccn2)c2c1N(CC(=O)O)CCSC2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of methyl 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetate (0.300 g, 0.64 mmol) and lithium hydroxide (0.062 g, 2.6 mmol) in THF (10 mL) and water (5 mL) was stirred at rt for about 2 h. Then 1 M aqueous HCl (15 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method a) to give 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetic acid (0.160 g, 0.36 mmol, 56%) as a white solid: LC-MS (Table 1, Method b) Rt=6.57 min; m/z 449 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.73-2.91 (2 H, m) 3.40-3.63 (2 H, m) 3.92 (3 H, s) 4.12 (1 H, d, J=18.4 Hz) 4.21 (1 H, d, J=18.4 Hz) 5.95 (1 H, br s) 6.46 (1 H, s) 6.94 (1 H, d, J=8.4 Hz) 7.00-7.07 (2H, m) 7.40 (1H, d, J=2.1Hz) 7.58 (1H, td, J=7.5, 1.8 Hz) 7.72 (1H, d, J=7.9 Hz) 8.40 (1H, d, J=5.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OCC)(OCC)(OCC)[CH2:15][CH2:16][CH3:17]>>[Cl:1][C:2]1[C:11]2[N:10]([C:14]([CH2:15][CH2:16][CH3:17])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCCC(OCC)(OCC)OCC
Reactant: NNc1nc2ccccc2nc1Cl
Product: CCCc1nnc2c(Cl)nc3ccccc3n12
Temperature: 25 °C
Yield: 53 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (3.0 g., 0.015 mole), the product of Example 1, was stirred with triethyl orthobutyrate (27 ml.) at 100° C. for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filtration and washed with cyclohexane. The crude solid was taken up in chloroform and filtered to remove insoluble material. The chloroform solution was concentrated in vacuo to give a solid which was recrystallized from chloroform to give 1.96 g. (53% yield) of 4-chloro-1-n-propyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 173°-175° C. Mass spectrum: m/e, 246 (P).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13](OC(C)(C)C)=O>C(O)(=O)C>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: CC(C)(C)ON=O
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a mixture of 2-ethyl-5-nitroaniline (2 g, 12 mmol) in acetic acid (AcOH) (60 mL) at ambient temperature was added a solution of tert-butyl nitrite (t-BuONO) (1.8 mL, 12 mmol) in AcOH (8 mL). After stirring at ambient temperature for 1 h, AcOH was removed in vacuo. The resulting residue was dissolved in ethyl acetate (EtOAc), washed with Sat. NaHCO3, dried over Na2SO4, and concentrated to afford 3-methyl-6-nitroindazole (1.2 g).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[C:26]([C:50]([F:53])([F:52])[F:51])=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([C:35]([N:37]([CH3:43])[CH2:38][C:39]([O:41][CH3:42])=[O:40])=O)=[C:30]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])[CH:29]=[CH:28]2>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:23][O:24][C:25]1[C:26]([C:50]([F:53])([F:52])[F:51])=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([C:35](=[S:10])[N:37]([CH3:43])[CH2:38][C:39]([O:41][CH3:42])=[O:40])=[C:30]([O:44][CH2:45][C:46]([F:49])([F:48])[F:47])[CH:29]=[CH:28]2
Reactant: COC(=O)CN(C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)CN(C)C(=S)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Yield: 64 %

Procedure:
Lawesson's reagent (3.20 g, 0.6 eq) was added to a stirred solution of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester, prepared by the process of Example 3, Step 1 (6.00 g, 13.2 mmol) in toluene (60 mL) at room temperature under argon. The reaction was heated to reflux for 111/2 hours, with more Lawesson's reagent (4.8 g, 0.9 eq) added in two portions after 21/4 and 83/4 hours. The reaction was cooled to room temperature and diluted with methylene chloride (300 mL). The crude reaction mixture was preabsorbed onto silica gel and flash chromatographed (petroleum ether→7:3 petroleum ether:ethyl acetate eluent gradient, silica) to provide the product as a yellow foam (3.94 g, 64%). A small sample was washed with petroleum. The filtrate was evaporated to dryness to provide a yellow solid for analysis, m.p. 104°-105° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([C:5]1[N:6]=[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCCN3CCCC3)c2n1
Yield: 80.8 %

Procedure:
A solution of 5-butyl-N-(2,4-dimethoxybenzyl)-3-(6-(pyrrolidin-1-yl)hex-1-yn-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (20 g, 40.8 mmol) in ethanol (500 mL) was hydrogenated over Pd—C (5 g, 4.70 mmol) for 4 hour (H2 uptake complete). The mixture was filtered through Hyflo and evaporated. The residue in DCM (30 mL) was purified on a 120 g silica cartridge (Redisep Gold) eluted with toluene-ethanol-NH3 (85/15/1.5) in 7 batches-taking off product and lower running impurity and recycling the cartridge each time (total volume˜3 liters). Evaporation of appropriate fractions gave the title compound as a yellow gum (16.3 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[F:20][C:21]1[C:26]([NH:27][C:28]([C:30]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH:31]=2)=[O:29])=[C:25]([CH3:39])[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C>[F:20][C:21]1[C:26]([NH:27][C:28]([C:30]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH:31]=2)=[O:29])=[C:25]([CH3:39])[C:24]([C:2]2[CH:3]=[C:4]([NH:9][C:10]3[CH:19]=[C:13]4[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]4[N:11]=3)[C:5](=[O:8])[NH:6][N:7]=2)=[CH:23][CH:22]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2ccccc2s1
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)[nH]n2)ccc(F)c1NC(=O)c1cc2ccccc2s1
Yield: 49.8 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (225 mg, 0.80 mmol), N-(6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (463 mg, 1.13 mmol), DME (5 mL) and 1M aqueous sodium carbonate (2 mL). After bubbling Argon while sonicating for 30 sec, Pd(PPh3)4 (65 mg, 0.06 mmol) was added. The mixture was subjected to microwave irradiation at 150° C. for 20 min. After this time, ethyl acetate (10 mL) and water (10 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound N-{6-fluoro-2-methyl-3-[5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phenyl}-1-benzothiophene-2-carboxamide (211 mg) in 50% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]([N+:20]([O-])=O)=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](N)[CH2:27][CH2:28][CH3:29]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]([NH:20][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCNc1cc2c(cc1[N+](=O)[O-])C1CC2CN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (500 mg, 1.43 mmol) and 1-butylamine (1.42 mL, 14.3 mmol) were combined in THF (5 mL) and stirred 4 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with H2O (3×30 mL) then dried (Na2SO4), filtered and concentrated to an oil. This oil was passed through a Silica gel filter column to remove baseline impurities eluting with 30% ethyl acetate/hexanes (510 mg, 1.41 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][C@H:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(Nc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccccc1

Procedure:
2-Chloro-6-[(α-methylbenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (S)-α-methylbenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N
Agent: Cl[Sn]Cl
Solvent: O
Product: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-diethylamino-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example C27) (1.66 g, 4.96 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an off-white solid (1.38 g, 91%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([O:11]C(=O)C)[CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[OH:11][C:9]1[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(OC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of acetic acid 5-acetylamino-2-nitro-phenyl ester (20.5 g, 85.77 mmol) and potassium carbonate (26 g, 188.4 mmol) in methanol (200 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water (250 mL) was added and the resulting mixture was acidified by addition of concentrated hydrochloric acid. The solid which crushed out was triturated, collected by filtration, washed with water and dried under vacuum to afford N-(3-hydroxy-4-nitro-phenyl)-acetamide.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O>[CH2:16]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:17]
Reactant: CCI
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(F)c1F
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
2,3-difluorophenol 3a (4 g, 30.7 mmol) was dissolved in 60 mL acetone, followed by addition of potassium carbonate (6.36 g, 46.1 mmol) and ethyl iodide (3.19 mL, 39.9 mmol). The reaction mixture was stirred for 5 hours at 70° C. Thereafter, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 100 mL ethyl acetate, and washed with water (100 mL) and saturated sodium chloride solution (100 mL), and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-ethoxy-2,3-difluoro-benzene 3b (4.82 g, yellow grease), yield: 99.4%. 1H NMR (400 MHz, CDCl3): δ 6.95-6.89 (m, 1H), 6.78-6.71 (m, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: [C:1]([N:4]([CH3:19])[C:5]1[CH:6]=[C:7]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]([CH3:19])[C:5]1[CH:6]=[C:7]([N:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([NH2:11])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N(C)c1cc(N(C)C(C)=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N(C)c1cc(N)cc(N(C)C(C)=O)c1
Yield: 94.4 %

Procedure:
0.19 g (0.00072 mol) of N-[3-(acetyl-methyl-amino)-5-nitro-phenyl]-N-methyl-acetamide was dissolved in 15 ml of ethanol, treated with 0.019 g of Pd/C (10%) and hydrogenated with hydrogen gas at room temperature for 2 hours. The catalyst was filtered off, the solvent was distilled off and the residue was chromatographed on silica gel with ethyl acetate. There was obtained 0.16 g (94%) of N-[3-(acetyl-methyl-amino)-5-amino-phenyl]-N-methyl-acetamide as white crystals; m.p.: 179-181° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].S(OC)(O[CH3:18])(=O)=O>>[CH3:18][O:10][C:4]1[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1c(O)cc(F)c(F)c1F
Product: COc1cc(F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
Staring from 3,4,5-trifluoro-2-nitrophenol and dimethyl sulfate in place of allyl bromide and using a procedure analogous to that used to prepare Intermediate 6,3,4,5-trifluoro-2-nitro-phenyl methyl ether was prepared.