Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:16]1[CH:17]=[C:2]([Br:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:20])[CH2:25]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cc(Br)cc3o2)cc1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cc(Br)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
A mixture of 6-bromo-2-p-tolylbenzoxazole-4-carboxylic acid (85 mg, 0.26 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (85 mg, 0.31 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98 mg, 0.51 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.12 mL, 1.02 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) followed by recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide (30 mg, 25%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.94 (d, J=7.3 Hz, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.83 (d, J=1.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.63-4.50 (m, 1H), 3.12 (d, J=10.6 Hz, 2H), 2.70-2.55 (m, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 2.20-1.95 (m, 2H), 1.65-1.45 (m, 4H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 468 (M+H); HPLC 98.4% (AUC), tR=14.06 mm.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1[N:4]=[CH:5][N:6]([CH2:8][C:9]#N)[CH:7]=1.[OH:11][C:12]1[CH:19]=[C:18]([N:20]2[N:24]=[C:23]([CH3:25])[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)[CH:17]=[CH:16][C:13]=1[CH:14]=O.C(O)(=[O:34])C>CN(C)C=O>[Cl-:1].[CH3:2][N+:3]1[N:4]=[CH:5][N:6]([C:8]2[C:9](=[O:34])[O:11][C:12]3[C:13]([CH:14]=2)=[CH:16][CH:17]=[C:18]([N:20]2[N:24]=[C:23]([CH3:25])[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:21]2)[CH:19]=3)[CH:7]=1
Reactant: Cc1nn(-c2ccc(C=O)c(O)c2)nc1-c1ccccc1
Reactant: CC(=O)O
Reactant: C[n+]1cn(CC#N)cn1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc3cc(-n4cn[n+](C)c4)c(=O)oc3c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
3.48 g (22.0 mmols) of 1-methyl-4-cyanomethyl-1,2,4-triazolium chloride are added to 6.02 g (20.0 mmols) of the Na salt of 2-hydroxy-4-(4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)-benzaldehyde and 4.80 g (80.0 mmols) of glacial acetic acid in 20 ml of anhydrous dimethylformamide, under an N2 atmosphere, and the mixture is stirred for 24 hours at room temperature. The precipitate is filtered off under suction, washed with dimethylformamide and dried: 3.60 g (43%) of a pale yellow powder. Recrystallisation from water yields 2.90 g (35%) of 1-methyl-4-[7-(4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)-coumarin-3-yl]-1,2,4-triazolium chloride in the form of small pale yellow crystals of melting point 249°-252° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([NH2:9])[CH:6]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COc1cc(Cl)c(I)cc1N
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: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (4.1 g, 14.5 mmol), 2,5-dichlorophenylboronic acid (3.3 g, 17.4 mmol), Pd(PPh3)4 (500 mg, 1.45 mmol) and Na2CO3 (4.7 g, 43.5 mmol) in 1,4-dioxane (150 mL) and water (15 mL) was stirred at 80° C. under argon for 16 h. The mixture was allowed to cool to room temperature, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (3.3 g, 75.8% yield) as an off-white solid.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)[C:14]([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[C:14]([C:17]1[O:12][C:11]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:2]=1)([CH3:16])([CH3:15])[CH3:13]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(C(=O)O)cccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.30 g, 1.28 mmol) and pivaloyl chloride (0.16 mL, 1.28 mmol) in dichloromethane (10 mL) was added triethylamine (0.72 mL, 5.12 mmol) dropwise, then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (240 mg, 1.26 mmol). The reaction mixture was then heated to reflux for 1.5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-tert-butylbenzoxazole-4-carboxylic acid (0.15 g, 53%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.71 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 1.45 (s, 9H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: Cl[CH:2]1[C:6](=O)[CH2:5][O:4][C:3]1=[O:8].[NH2:9][C:10]([NH2:12])=[S:11].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[NH2:9][C:10]1[S:11][C:6]([C:5]([O:16][CH:13]([CH3:15])[CH3:14])=[O:4])=[C:2]([CH2:3][OH:8])[N:12]=1
Reactant: O=C1COC(=O)C1Cl
Reactant: NC(N)=S
Reactant: CC(C)O
Product: CC(C)OC(=O)c1sc(N)nc1CO

Procedure:
A solution of 5 g (37 mmol) of 3-chlorofuran-2,4(3H,5H)-dione and 3.7 g (49 mmol) thiourea in 30 mL isopropanol was heated at refluxed overnight. Solvent was removed and the residue was dissolved in water. The solution was treated with aqueous Na2CO3 precipitating solids. The solids were filtered, washed with water and dried in vacuum. NMR: 1.2 (d, 6H), 4.55 (d, 2H), 4.9 (t, 1H), 5.0 (m, 1H), 7.7 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH:3]([OH:15])[CH2:4][O:5][C:6]1[C:7](Cl)=[N:8][C:9]([Cl:13])=[N:10][C:11]=1[Cl:12].C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:13][C:9]1[N:10]=[C:11]([Cl:12])[C:6]([O:5][CH2:4][CH:3]([OH:15])[C:2]([CH3:1])([CH3:17])[CH3:16])=[C:7]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:8]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)C(O)COc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 3,3-dimethyl-1-(2,4,6-trichloro-pyrimidin-5-yloxy)-butan-2-ol (275 mg, 1.05 mmol) in IMS (3 mL) was added triethylamine (291 μL, 2.09 mmol) followed by morpholine (100 μL, 1.15 mmol) and stirred at RT for 2 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution then extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) then concentrated in vacuo giving 1-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-3,3-dimethyl-butan-2-ol (255 mg, 77%). LCMS: RT=3.57 min, [M+H]+=350/352/354.
Reaction SMILES: [N-:1]=[C:2]=[S:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])[CH:16]=1.O>CC(C)=O>[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:22]=[C:23]([NH:24][C:2]([NH:1][C:5](=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[S:3])[CH:25]=[CH:26][CH:27]=2)[CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccnc(-c2cccc(N)c2)c1
Reactant: [N-]=C=S
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccnc(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of ammonium isothiocyanate (142 mg) in acetone (3 ml) was added benzoyl chloride (0.199 ml) at 50° C., and the mixture was stirred at 50° C. for 10 minutes. To the resultant suspension was added a solution of 3-(4-methylpyridin-2-yl)aniline (300 mg) in acetone (6 ml) dropwise, and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration and dried to give N-(3-(4-methylpyridin-2-yl)phenyl)-N′-benzoylthiourea (557 mg).
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH:23]([CH3:34])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH:23]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH3:34])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCN1CCC(O)CC1)Oc1ccccc1[N+](=O)[O-]
Reactant: ClC(c1ccccc1)c1cccs1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCN1CCC(OC(c2ccccc2)c2cccs2)CC1)Oc1ccccc1[N+](=O)[O-]

Procedure:
The procedure of Example 36 (a) was repeated except for using phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)-3-methylpropyl]piperidine.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:11][N:12]=[N+]=[N-])[CH2:10][O:9][CH2:8][O:7][CH2:6]1)=[N+]=[N-]>[Pd].C(O)C>[O:7]1[CH2:6][C:5]([CH2:11][NH2:12])([CH2:4][NH2:1])[CH2:10][O:9][CH2:8]1
Reactant: [N-]=[N+]=NCC1(CN=[N+]=[N-])COCOC1
Agent: [Pd]
Solvent: CCO
Product: NCC1(CN)COCOC1
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of 1.95 g of 5,5-bis(azidomethyl)-1,3-dioxane, 0.5 g of 10% palladium on calcium carbonate and 40 ml of ethanol was reduced for 2 hours and then filtered. The filtrate was evaporated, giving 1.41 g of 1,3-dioxane-5,5-dimethanamine as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=O)[CH:3]=[N:2]1.[CH3:11]CN(C(C)C)C(C)C.[NH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:26][C:27]=1[CH3:28].CCCP(=O)=O>CN(C=O)C.C(OCC)(=O)C.O>[NH:2]1[CH:3]=[C:4]([C:6]([NH:20][CH2:21][C:22]2[C:23]([CH3:11])=[CH:24][C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[N:26][C:27]=2[CH3:28])=[O:8])[CH:5]=[N:1]1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CN
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn[nH]c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The starting material ethyl pyrazole-4-carboxylate was saponified in analogy to Example 157, Step a), To a solution of the free acid (1 g, 5.86 mmol) in DMF (40 ml) were added DIPEA (4.10 ml, 23.46 mmol) and tert-butyl (5-(aminomethyl)-6-methylpyridin-2-yl)carbamate (1.531 g, 6.45 mmol). At 0° C., propylphosphonic anhydride (50% in DMF, 3.42 ml, 5.86 mmol) was added dropwise. Reaction mixture was stirred for 30 min at 0° C., then diluted with ethyl acetate and water. Phases were separated and organic layer was washed with NaHCO3 sat. solution and brine. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the crude material, which was purified by silicagel chromatography (DCM/MeOH from 100/0 to 9/1 in 30 min) to afford the title compound. HPLC (Method G) Rt=1.209 min, MS (Method V) [M+H]+=332.3.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].CS(O[CH2:27][CH2:28][O:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[N:33][C:34]([CH3:40])=[N:35]2)(=O)=O>>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:27][CH2:28][O:29][C:30]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:31]=4[CH:32]=[N:33][C:34]([CH3:40])=[N:35]5)[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCOc2ccc(CN3CCNCC3)cc21
Reactant: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Product: Cc1ncc2c(OCCN3CCN(Cc4ccc5c(c4)N(S(C)(=O)=O)CCO5)CC3)cccc2n1

Procedure:
The title compound was prepared from 4-methanesulfonyl-6-(piperazin-1-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazine and 5-(2-(methanesulfonyloxy)ethoxy)-2-methylquinazoline following the method of Example 1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: N#Cc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1CN=[N+]=[N-]

Procedure:
A solution of 2-bromomethyl-benzonitrile (1.0 g, 5.1 mmol) and sodium azide (0.40 g, 6.1 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 h. Ethyl acetate was added and the reaction mixture was washed with water and brine. Drying and solvent evaporation gave 2-azidomethyl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ 7.71 (d, 1H, J=7.7 Hz), 7.64 (m, 1H), 7.53 (d, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.6 Hz), 4.62 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:17][NH2:18]>O>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:17][N:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1O
Reactant: NN
Solvent: O
Product: Cc1ccc(C2=NNC(=O)CC2)cc1O

Procedure:
A stirred suspension of 3-(3-hydroxy-4-methylbenzoyl) propionic acid (6.75 g, 0.032 mole) in water (40 ml) was treated with hydrazine hydrate (2.4 ml, 0.048 mole) and heated under reflux for 1 hour. The mixture was diluted with water (50 ml), cooled, and the product collected then washed with water. (6.36g, 96%, m.p. 215°-218°C). Crystallisation from ethanol gave pure 6-(3-hydroxy-4-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone, m.p. 216°-218°C
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[N:6]1[CH:7]=[CH:8][C:3]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1ccncc1
Agent: Cl
Product: N#Cc1ccc(-c2ccncc2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 11 using 4-bromopyridine hydrochloride instead of 1-bromo-3-pentyloxybenzene and 4-cyanophenylboronic acid instead of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-benzyl]carbamate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23](=[O:37])[CH2:24][CH2:25][C:26]4[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.OCC(N1CCCC1C(F)(F)F)=O.O[CH2:52][C:53]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:54]>>[N:55]1([C:53](=[O:54])[CH2:52][O:33][C:32](=[O:34])[CH2:31][O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:23]([N:20]3[CH2:21][CH2:22][C:15]4([NH:14]/[C:13](=[N:12]/[C:10]([C:3]5[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=5)=[O:11])/[NH:17][CH2:16]4)[CH2:18][CH2:19]3)=[O:37])=[CH:36][CH:35]=2)[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)cc4)CC3)N2)nc1Cl
Reactant: O=C(CO)N1CCOCC1
Agent: O=C(CO)N1CCCC1C(F)(F)F
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)OCC(=O)N5CCOCC5)cc4)CC3)N2)nc1Cl

Procedure:
The title compound was prepared by an analogous method to Example 4.0, replacing 3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid with [4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (Intermediate B), and 2-hydroxy-1-(2-(trifluoromethyl)pyrrolidin-1-yl)ethanone (Int. D) with 2-hydroxy-1-morpholin-4-yl-ethanone; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (2H, br hump), 7.15 (2H, d), 6.87 (2H, d), 6.72 (2H, br s), 4.93 (2H, s), 4.82 (2H, s), 3.63 (2H, m), 3.56 (4H, m), 3.42 (2H, m), 3.40 (8H, m), 2.74 (2H, t), 2.59 (2H, t), 1.59 (4H, m). LC-MS Rt 3.10 mins; 658.4 [M+H]+, Method 10minLC_v002.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[O:4].[F:6][C:7]1[CH:8]=[C:9]([OH:17])[CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=1)[O:17][CH2:2][C:3](=[O:4])[CH3:5]
Reactant: CS(=O)(=O)c1cc(O)cc(F)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)COc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
1-Chloroacetone (95%, 2.66 g, 27.34 mmol) was added to a stirred solution of 3-fluoro-5-methylsulfonyl-phenol (80%, 1.3 g, 5.46 mmol) and potassium carbonate (2.26 g, 16.40 mmol) in dry dimethyl formamide (10 ml), the mixture was heated to 120° C. for 20 minutes, the mixture was allowed to cool to ambient temperature and water (100 ml) was added. The aqueous phase was extracted with ethyl acetate (3×100 ml), the combined organic phase was washed with LiCl (5% aqueous solution, 4×50 ml), brine (50 ml) and dried with Na2SO4 and evaporated. Purification on flash chromatography (isooctane: ethyl acetate 1:0 to 3:2). 0.905 g, 67%. MS m/z (relative intensity, 70 eV) 246 (M+, 79), 204 (55), 203 (bp), 141 (30), 94 (67).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][OH:20])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21]I>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[CH2:19][O:20][CH3:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1CO
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@@H]1Cc2ccccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a slurry of sodium hydride (60%) (1.623 g, 40.5 mmol, 1.3 eq) in THF (15 mL) was added (S)-2-hydroxymethyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7.760 g, 31.1 mmol, 1 eq) (J. Org. Chem, 62, 7679, 1997) in THF (100 mL) and the mixture was stirred at room temperature for 1 hr. Methyl iodide (3 mL, 48.2 mmol, 1.5 eq) was added and the reaction was stirred at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The crude residue purified by column chromatography using ethyl acetate/hexanes (10/90) as an eluent to give the title compound as a colorless oil (3.863 g, 47% ). NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:24])=[N-]>CO.CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([NH:20][CH3:21])[N:13]=2)[CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC)n1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CO
Product: CNc1cc(N(C)S(=O)(=O)c2ccc(N)cc2)nc(NC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
0.65 g (0.0021 mol) of 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in a mixture of 100 ml of methanol and 400 ml of dimethylformamide and treated with 60 ml of a solution of diazomethane in diethyl ether. The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off and the residue was chromatographed over 50 g of SiO2 with 5% of methanol in methylene chloride as the eluent. There was obtained 0.24 g (35%) of 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-N-methyl-benzenesulfonamide as a yellow solid; m.p.: 79-80° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[F:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([F:42])[CH:44]=3)(=[O:51])=[O:50])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 445 mg, 91%).