Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>O1CCCC1>[C:1]([N:5]([CH3:29])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)(C)C)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To a solution of methyl 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (115 mg, 0.33 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (65 mg, 2.71 mmol) at 0° C. and then stirred for 10 minutes at room temperature. Methyliodide (185 mg, 1.30 mmol) was then added with stirring, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water (50 mL), adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (3×80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the residue. Purification via Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm] afforded 3-(tert-butyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (8.20 mg, 7.13%).
Reaction SMILES: C([N:8]([CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[CH2:9][CH2:10][OH:11])C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)([O-])O.[K+].O>ClCCl>[CH2:28]([O:27][C:25]([N:8]([CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[CH2:9][CH2:10][OH:11])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1Nc2ccccc2C1CCN(CCO)Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C1Nc2ccccc2C1CCN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
3-[2-[N-Benzyl-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one (463 mg) was dissolved in dichloromethane (9.2 ml), added with benzyl chloroformate (0.51 ml) and potassium hydrogencarbonate (358 mg) and stirred at room temperature for 24 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 ml), added with 1 N aqueous sodium hydroxide (2.2 ml) and stirred for 30 minutes. The reaction mixture was added with water (50 ml) and extracted twice with dichloromethane (40 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 272 mg of the title compound. Yield: 52%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:32].C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:14](=[O:16])[CH2:13][CH2:12][C:10]3[O:9][N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:11]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:32]
Reactant: NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Reaction time: 2 h

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.136 g) and N,N′-carbonyldiimidazole (0.114 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(4-Chloro-3-fluorobenzyl)-4-piperidinamine (0.150 g) was then added and left to stir for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This was triturated with diethyl ether which caused product the to crystallise. After filtration, the product was washed with diethyl ether and dried to N-[1-(4-chloro-3-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide. m.p. 132° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH2:9].[CH3:12][O:13][CH:14]([O:19][CH3:20])[C:15](OC)=[O:16].CCN(C(C)C)C(C)C>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][NH:9][C:15](=[O:16])[CH:14]([O:19][CH3:20])[O:13][CH3:12]
Reactant: NCc1cc(Br)ccc1F
Reactant: COC(=O)C(OC)OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(OC)C(=O)NCc1cc(Br)ccc1F
Temperature: 60 °C

Procedure:
A mixture of 5-bromo-2-fluorobenzylamine hydrochloride (15.0 g, 62 mmol), methyl dimethoxyacetate (10.0 g, 75 mmol), and DIPEA (10.3 mL, 62 mmol) in methanol (15 mL) was heated at 60° C. for 16 h in a bomb apparatus. After cooling to RT, the solvent was evaporated and DCM (150 mL) was added. The solution was washed with water (2×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. It was purified by column chromatography on silica gel using EtOAc/Hexanes (1:1) to give the title compound. 1H NMR (CDCl3, 300 MHz) δ=3.42 (s, 6H), 4.53 (d, J=4.8 Hz, 2H), 4.81 (s, 1H), 6.96 (t, J=6.8 Hz, 1H), 7.40-7.42 (m, 1H), 7.51-7.54 (m, 1H). MS(ES+): m/z=305.73/307.69 [MH+]. HPLC: tR=2.89 min (polar—5 min, ZQ2).
Reaction SMILES: [CH2:1]([C:3]([CH:5]=[CH2:6])=[O:4])[CH3:2].C[O-].[Na+].[N+:10]([CH3:13])([O-:12])=[O:11]>CO>[N+:10]([CH2:13][CH2:6][CH2:5][C:3](=[O:4])[CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: C=CC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)CCC[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To ethylvinylketone (41.4 g, 493 mmol) in MeOH (150 mL) and nitromethane (160 mL) was added sodium methoxide (ca. 123 mmol; 27 mL of a 25% solution in MeOH). The mixture was warmed to −10° C. over 30 min. After 1.5 h at −10° C., the mixture was quenched with saturated NH4Cl (250 mL) and water (250 mL). The mixture was pured into a separatory funnel and the lower organic layer was removed. The aqueous portion was extracted with CH2Cl2 (2×250 mL) and the combined organic portions were dried with MgSO4 and concentrated. The resultant liquid was reconcentrated from toluene (2×250 mL) followed by methanol (1×250 mL) to yield the desired material.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23](O)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl-].[NH4+].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([NH2:30])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(=O)O)cc1OCC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(N)=O)cc1OCC2

Procedure:
Following the procedures of Example 215, 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid, ammonium chloride, and HATU were reacted to give 351. M/z 353.1, calc. 352.16. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 7.91 (s, 2H), 7.48 (s, 1H), 7.04 (d, J=8.2, 1H), 6.97 (s, 1H), 6.92 (s, 1H), 5.95-5.81 (m, 1H), 4.50 (d, J=5.8, 4H), 3.38 (s, 2H), 1.48 (d, J=6.5, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[NH2:12][C:13](N)=[O:14]>C(O)(=O)C>[Cl:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:13]([NH2:12])=[O:14]
Reactant: NC(N)=O
Reactant: Nc1cc(C(=O)O)ccc1Cl
Solvent: CC(=O)O
Product: NC(=O)Nc1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A stirred solution of 3-amino-4-chlorobenzoic acid (34.2 g, 200 mmol) and urea (24 g, 400 mmol) in glacial acetic acid (200 mL) was heated at 100° C. for 24 h. The mixture was allowed to cool to room temperature and the resulting precipitate was separated by filtration, washed with water (2×100 mL) and diethyl ether (2×100 mL), then air dried to give 35 g of 4-chloro-3-ureido-benzoic acid as a grey solid that was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>O1CCCC1.C1(C)C=CC=CC=1>[F:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[C:8]([I:12])[CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(F)cc(I)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cc(I)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg (1.78 mmol) of 2-amino-3-fluoro-5-iodo-benzoic acid in 5.0 mL tetrahydrofuran was added 1.4 mL (2.67 mmol) of 20% w/v solution of phosgene in toluene. The reaction was stirred for 16 hours at room temperature. The solution was concentrated to dryness to afford 550 mg (1.79 mmol, quantitative yield) of 8-fluoro-6-iodo-1H-benzo[d][1,3]oxazine-2,4-dione as a brown powder. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.09 (dd, 1H), 7.98 (s, 1H).
Reaction SMILES: [H-].[Na+].CS(C)=O.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Cl:16].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:15][C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([Cl:16])[CH:11]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Sodium hydride (60 wt %, 320 mg) was added to dimethyl sulfoxide (3.6 ml), and the mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-3-chlorophenol hydrochloride (720 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (600 mg) was then added thereto, and the mixture was stirred at 105° C. for 22 hr. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 533 mg (yield 66%) of the title compound.
Reaction SMILES: C([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:13])[CH:4]=1)=O.[C:14]([NH:17][CH2:18][C:19]([OH:21])=[O:20])(=O)[CH3:15].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[O:13]=[C:5]1[CH2:4][C:3](=[C:18]2[C:19](=[O:20])[O:21][C:14]([CH3:15])=[N:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1
Reactant: O=Cc1cc(=O)[nH]c2ccccc12
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=C2CC(=O)Nc3ccccc32)C(=O)O1

Procedure:
17 Grams of 4-formylcarbostyril, 18 g of N-acetylglycine, 7 g of anhydrous sodium acetate and 100 ml of acetic anhydride were heated at 110° C. to make a homogeneous solution, further the solution was refluxed for 1.5 hours. After cooled the reaction mixture, the reaction mixture was poured in a cold water and the crystals precipitated were collected by filtration. The crystals were washed with cold water, then recrystallized from ethanol-chloroform to obtain 10 g of 4-(1,2-dihydro-2-oxo-4-quinolyliden)-2-methyl-5-oxazolone.1/2-hydrate.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[Na].[C:6]([C:8]1[C:9]([SH:21])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:13]=1[CH3:14])#[N:7].II>C(O)C>[C:6]([C:8]1[C:9]([S:21][S:21][C:9]2[C:8]([C:6]#[N:7])=[C:13]([CH3:14])[CH:12]=[C:11]([C:3]3[CH:2]=[CH:20][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[N:10][C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][C:13]=1[CH3:14])#[N:7]
Reactant: CC[O-]
Reactant: Cc1cc(-c2ccccc2)nc(S)c1C#N
Agent: II
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cc(-c2ccccc2)nc(SSc2nc(-c3ccccc3)cc(C)c2C#N)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
An ethanolic solution containing sodium ethoxide was prepared by dissolving 0.74 g of metallic sodium in 70 ml of ethanol. To the solution was added 7.28 g of 3-cyano-4-methyl-6-phenyl-2-pyridinethiol. The mixture was stirred at room temperature for about 20 minutes to give a yellowish homogeneous solution. To this solution was added dropwise with stirring at room temperature 60 ml of ethanol containing 4.09 g of iodine. With addition, colorless crystals began to precipitate and there was obtained a suspension at the time of completion of the addition. After completion of the addition, stirring was continued for about 2 hours at room temperature. The reaction mixture was then filtered and the collected substance was dried to give 7.00 g of brownish crystals. The obtained crystals were recrystallized from benzene. The crystals recrystallized had a melting point of 200°~201° C and were identified by the elemental analyses and IR spectrum as bis(3-cyano-4-methyl-6-phenyl-2-pyridyl) disulfide.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([OH:11])[CH:7]=[CH:8][CH2:9][OH:10].N1C=CC=CC=1>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[O:10][CH2:9][CH:8]=[CH:7][CH2:6][O:11][C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: OCC=CCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)OCC=CCOC(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine methyl chloroformate (7.04 g, 80.0 mmol) in THF (70 mL) and add dropwise to a ice-water cold solution of 2-buten-1,4-diol (majority Z form) (19.7 g, 208 mmol) and pyridine (16.5 g, 208 mmol) in THF (150 mL). Warm the mixture to room temperature and stir for 20 hours. Remove the pyridine salt by filtration and concentrate the filtrate to a residue. Dissolve the residue with CH2Cl2 and wash sequentially with 1 N HCl and brine. Dry the organic layer over Na2SO4 and concentrate the solvent in vacuo to give a residue. Purification by chromatography using hexanes: EtOAc=12:1 as the eluents give the title compound: 1H NMR (CDCl3): δ5.82–5.79 (m, 2H), 4.75 (d, J=4.8 Hz, 4H), 3.79 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[C:16]([N:23]1[CH2:24][CH2:25][N:26]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH2:27][CH2:28]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixture of 2-chloro-4-(chloromethyl)pyridine (500 mg, 2.05 mmol) and K2CO3 (1.14 g, 4 equiv) in DMF (50 ml), was added N-Boc-piperazine (558 mg, 1.1 equiv.). The mixture was stirred at rt for 1 h, after which TLC showed that no starting materials remained. The DMF was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was collected, dried over anhydrous Na2SO4, concentrated, and applied onto a silica gel column. The title compound (570 mg, yield 91%) was obtained as a colorless gel.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH:8][C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([CH3:16])[CH:18]=2)[N:7]=[CH:6][N:5]=1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 2, 6-chloro-4-(3'-methylanilino)pyrimidine was reacted with 3-methylaniline to give 4,6-di-(3'-methylanilino)pyrimidine in 25% yield, m.p. 242°-244° C.;
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][Cl:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:23][CH2:24][Cl:25]
Reactant: CNCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(CN(C)CCCl)cccc2c1=O
Reaction time: 12 h

Procedure:
A mixture of 22 g of Intermediate XX, 66 ml of 1-bromo-2-chloroethane and 11 g of anhydrous potassium carbonate in 88 ml of dimethylformamide was stirred at 20°-25° C. for 12 hours. The reaction mixture was then poured into 600 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried on anhydrous sodium sulfate and acidified with ethanolic hydrogen chloride. The solvent and the excess 1-bromo-2-chloroethane were distilled off in vacuo at 70°-80° C. The residue was taken up in cold 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic solution was washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo at 25°-30° C. The crude title product was purified by flash chromatography on silica gel, eluting with ethyl acetate:petroleum ether (7:3), to give 18 g of the title compound melting at 118°-120° C. after crystallization from ethanol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1>[CH2:24]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)[CH3:25]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Temperature: 65 °C
Reaction time: 72 h

Procedure:
(3aR,4S,6aS)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (120 mg, 0.359 mmol) from Step A of Example 256, iodoethane (0.287 mL, 3.59 mmol), and triethylamine (0.750 mL, 5.38 mmol) were in tetrahydrofuran (1 mL). The reaction was stirred at 65° C. for 3 days, and then the solvent was removed in vacuo. The residue was diluted with dichloromethane (5 mL), and addition of saturated aqueous sodium bicarbonate gave the products as a solid. This material was purified using a 12 g silica gel cartridge with a gradient of 0-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give two products. The second product was further purified on 4×0.25 mm preparative thin-layer chromatography plate eluting with 6% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.17-8.19 (m, 2H), 7.93-7.95 (m, 2H), 3.38 (dd, J=9.8, 3.1 Hz, 1H), 3.15 (dd, J=9.6, 3.2 Hz, 1H), 3.06 (dd, J=9.8, 8.0 Hz, 1H), 2.96 (dd, J=9.6, 7.7 Hz, 1H), 2.78 (q, J=6.1 Hz, 1H), 2.44-2.58 (m, 4H), 2.25-2.33 (m, 1H), 1.85-1.92 (m, 1H), 1.75-1.85 (m, 1H), 1.16-1.34 (m, 2H), 1.05 (t, J=7.1 Hz, 3H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccccc1CBr
Reactant: OCCc1cccc(O)c1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1cccc(CCO)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
3-(2-Hydroxyethyl)phenol (1.0 g, 7.24 mmol) and methyl 2-(bromomethyl)benzoate (1.74 g, 7.6 mmol) were dissolved in acetonitrile (10 ml). Potassium carbonate anhydrous (2.0 g, 14.48 mmol) was added. After stirring at 60° C. for three hours PS-trisamine was added (0.3 eq) and was stirred overnight. The PS-trisamine was filtered off and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic layer was washed with 3 portions of water (3×10 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 1.99 g of methyl 2-{[3-(2-hydroxyethyl)phenoxy]methyl}benzoate (yield 90%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[S:7](=[O:9])(=[O:8])[CH:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C:5]2([CH3:22])[N:4]=[C:3]1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CCOC(C)=O.CCO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][CH:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:31])([CH3:1])[C:3]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:4][C:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(C)c3cc([N+](=O)[O-])ccc3OCCC2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC2(C)c3cc(N)ccc3OCCC2S(=O)(=O)C1(C)C
Yield: 74.7 %

Procedure:
A solution of tert-butyl ((4aRS,11bRS)-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (100 mg, 0.221 mmol) in EtOAc (2 ml) and EtOH (2 ml) was hydrogenated under hydrogen balloon in the presence of palladium, 10% wt. on activated carbon (50 mg, 0.047 mmol) for 30 min. The mixture was filtered through the plug of Celite, filter cake was washed with ethyl acetate. The combined filtrate was concentrated ton afford crude tert-butyl ((4aRS,11bRS)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (70 mg, 0.165 mmol, 75.0% yield) which was used without further purification.