Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:32][C:33]([NH2:36])([CH3:35])[CH3:34]>CS(C)=O.O>[C:33]([NH:36][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH3:35])([CH3:34])[CH3:32]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CC(C)(C)N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)(C)C)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (163 mg, 1.26 mmol) and 2-methylpropan-2-amine (461.3 mg, 6.32 mmol) with stirring overnight at 90° C. in an oil bath. The reaction mixture was cooled to room temperature, diluted with H2O (150 mL), extracted with ethyl acetate (3×80 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a light yellow solid (115 mg, 51%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:2]([O:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(C)cc1C

Procedure:
The product was generated via general protocol A using 1-bromotetradecane (44 mL, 0.149 mol), 2,4-dimethylphenol (19.5 mL, 0.164 mol), K2CO3 (82.4 g, 0.596 mol) and CH3CN (200 mL). Yielded 43.13 g (90.8%). 1H NMR (CDCl3, 600 MHz) δ: 7.00 (s, 1H, Ar—H), 6.94 (d, 3J=8.41 Hz, 1H, Ar—H), 6.75 (d, 3J=8.15 Hz, 1H, Ar—H), 3.97 (t, 3J=6.46 Hz, 2H, OCH2), 2.31 (s, 3H, Ar—CH3), 2.26 (s, 3H, Ar—CH3), 1.83 (p, 3J=7.3 Hz, 2H, O—CH2—CH2), 1.52 (p, 3J=7.6 Hz, 2H, O—CH2—CH2—CH2), 1.44-1.28 (m, 22H), 0.95 (t, 3J=7.05, 3H, CH2—CH3). 13C NMR (150 MHz) δ: 155.24, 131.45, 129.20, 126.88, 126.66, 111.08, 68.17, 53.41, 32.02, 31.90, 29.97, 29.79, 29.78, 29.76, 29.52, 29.50, 29.46, 26.24, 22.78, 20.47, 16.19, 14.19.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Br[CH:17](Br)[CH3:18]>CC(C)=O.O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH2:18][CH2:17]1
Reactant: CC(Br)Br
Reactant: CNc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCOc2ccccc21
Reaction time: 22 h
Yield: 85.1 %

Procedure:
0.97 g of 2-(N-methylamino)-phenol were dissolved in 50 ml acetone, followed by the addition of 2 g of K2CO3 dissolved in water. To this suspension was added slowly a solution of 2.66 g of dibromoethane in acetone. The reaction mixture was stirred for 22 hours under reflux. Acetone was evaporated and 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 3× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1 g of pure 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:19][CH:18]([O:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:20]
Reactant: COC(=O)c1[nH]ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]ccc1OC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
Methyl 3-hydroxy-1H-pyrrole-2-carboxylate (2.0 g, 0.014 moles) is dissolved in DMF (15 mL) under nitrogen. Potassium carbonate (2.8 g, 0.020 moles) is added followed by 2-bromopropane (5 mL, 0.05 moles) and the mixture is stirred at room temperature for 18 hours, then at 50° C. for 3 hours, then stirred into ice water (400 mL). The mixture is extracted with CH2Cl2 (3x) and the combined extracts are washed with brine (2x) and dried over MgSO4. Removal of the solvent under reduced pressure leaves the crude product as a crystalline residue. Recrystallization from ether gave the pure product (1.6 g); mp 77°-79° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][OH:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(N(CC)CC)C.C1COCC1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:35]([O:30][CH2:29][C:6]1([CH2:5][C:4]2[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=2)[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCCC3(COC(C)=O)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A catalytic amount of 4-dimethylaminopyridine was added to a mixture of {8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (80.0 mg), acetic anhydride (19.4 μL), triethylamine (28.6 μL) and THF (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and diluted with ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (72.5 mg).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([O:4][C:3](=[O:5])[CH:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:1])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: CC(Oc1cccc2[nH]ccc12)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C(C)Oc1cccc2[nH]ccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylindol-4-yloxyacetic acid (2 g) in N,N-dimethylformamide (20 ml) was added anhydrous potassium carbonate (2.02 g) and allyl bromide (1.27 ml), and the mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added water and ethyl acetate, then separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane—ethyl acetate) to give the title compound (1.88 g) having the following physical data.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:11]=[C:10]2[N:12]([CH2:16][CH3:17])[C:13]([NH2:15])=[N:14][C:9]2=[CH:8][CH:7]=1>C(O)C.[Pd]>[CH2:16]([N:12]1[C:10]2=[N:11][CH:6]=[CH:7][CH:8]=[C:9]2[N:14]=[C:13]1[NH2:15])[CH3:17]
Reactant: CCn1c(N)nc2ccc(Cl)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCn1c(N)nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
Ammonium formate (1.55 g, 24.6 mmol) is added to a solution of 5-chloro-3-ethyl-3H-imidazo[4,5-b]pyridin-2-amine (410 mg, 2.09 mmol) in ethanol (10 mL) containing 10% palladium on carbon (40 mg). The mixture is stirred at room temperature for 16 h. The reaction is filtered, concentrated under reduced pressure and the residue is purified via flash column chromatography using a gradient elution of 0-10% CH2Cl2/methanol to afford the title compound (192 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]2[S:17][C:18]([CH2:20][CH3:21])=[CH:19][C:9]=12.Cl.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.O.O1CCOCC1>[NH2:14][C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:9]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:10]2=[N:11][CH:12]=1
Reactant: CCc1cc2c(-c3ccccc3Cl)c([N+](=O)[O-])cnc2s1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(-c3ccccc3Cl)c(N)cnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a mixture of 4-(2-chlorophenyl)-2-ethyl-5-nitrothieno[2,3-b]pyridine (4.0 g), dioxane (25 ml) and conc. hydrochloric acid (12.5 ml) was added tin(II) chloride dihydrate (8.5 g). After stirring at room temperature for one hour, water was added to the mixture, which was made strong alkaline with 6N NaOH and then extraced with chloroform. The extract was washed with water and dried over MgSO4 and the solvent was distilled off. The residue was chromatographed on a silica gel column and eluted with hexane-ethyl acetate (4 : 1). The solvent was distilled off and to the residue was added hexane to obtain 5-amino-4-(2-chlorophenyl)-2-ethylthieno[2,3-b]pyridine (3.1 g, 85.6%) as crystals. The crystals were recrystallized from isopropyl ether to obtain colorless prisms, mp: 87°-88° C.
Reaction SMILES: [NH:1]1[C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=[N:2]1.[Br:11]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:3]1[C:4]2[CH:8]=[C:7]([C:9]#[N:10])[S:6][C:5]=2[NH:1][N:2]=1
Reactant: N#Cc1cc2cn[nH]c2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(Br)n[nH]c2s1
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 168 mg of 1H-thieno[2,3-c]pyrazole 5-carbonitrile in 5 mL of dimethylformamide was added 200 mg of N-bromosuccinimide at room temperature and stirred at this temperature for 2 hours. After adding 1 mL of 10% sodium thiosulfate aqueous solution, the solution was diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. This afforded 3.7 g of the title compound as a colorless oil. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10), to afford 220 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([NH:12][C:13](=[O:35])[N:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(OCC)C.[Ag]=O>[CH2:1]([O:34][C@@H:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N:14]([CH3:15])[C:13]([NH:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:35])[CH:17]=2)=[CH:27][CH:26]=1)[C:30]([O:32][CH3:33])=[O:31])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](O)C(=O)OC)cc2)c1
Agent: O=[Ag]
Solvent: CCOCC
Product: C=CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)NCCCCCCC)c2)cc1)C(=O)OC
Temperature: 40 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
58 μl (0.70 mmol) of allyl bromide are added to a mixture of 162 mg (0.70 mmol) of silver oxide and 200 mg (0.47 mmol) of methyl (S)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-hydroxypropanoate in 3 ml of diethyl ether. The reaction mixture is stirred at 40° C. for 24 hours. The mixture is filtered and then the solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20 up to 60/40). 180 mg of methyl (S)-2-allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=82%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C=C)[C:11]([C:16](F)(F)F)=[CH:10][C:9]=1[NH:20][C:21](=[O:38])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.[C:40](O)([C:42]([F:45])([F:44])[F:43])=O>C(Cl)Cl>[CH3:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:38])[NH:20][C:9]4[CH:10]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:12]([CH:11]=[CH2:16])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example M224) (300 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (133 mg, 56%).
Reaction SMILES: [C:1]1([CH2:11][NH:12][S:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([OH:26])=O)[CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:27]CCl>CN(C)C=O>[C:1]1([CH2:11][NH:12][S:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]([Cl:27])=[O:26])[CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a suspension of 3-{3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (15a) (0.32 g, 0.87 mmol) in dichloromethane (4 ml) oxalyl chloride (0.22 ml, 2.61 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give the title compound (0.33 g, 98%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.C(O)C.O>[F:32][C:33]1[CH:34]=[C:35]([CH:51]=[C:52]([F:54])[CH:53]=1)[CH2:36][N:37]1[CH:41]=[C:40]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:3]=2)[CH:39]=[N:38]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cc(F)cc(F)c3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 134.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, N-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (intermediate 9) (200 mg, 0.352 mmol) was coupled with 1-(3,5-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 8) (159 mg, 0.528 mmol) in sodium carbonate (112 mg, 1.05 mmol), PdCl2(dppf) (13 mg, 0.017 mmol) and toluene/ethanol/water (18/12/8 ml) to afford 300 mg of the crude product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N=C=NCCCN(C)C)C.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
2,4,5-Trifluorobenzoic acid (15 g, 85.2 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide (24.45 g, 128 mmol) and 4-dimethylaminopyridine (15.6 g, 128 mmol) were stirred in dichloromethane at room temperature for 15 minutes under an atmosphere of nitrogen. Methanesulfonamide (12.15 g, 128 mmol) and triethylamine (23.8 g, 254 mmol) were added and the reaction stirred at room temperature overnight. A 1M aqueous solution of hydrogen chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed sequentially with brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The resulting residue was recrystallised from a mixture of ethyl acetate and heptane to afford the title compound (7.8 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:19][CH2:18][C:11]3[N:12]=[N:13][C:14]([NH:16][NH2:17])=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:25])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:19][CH2:18][C:11]3[N:12]=[N:13][C:14]([NH:16][N:17]=[C:23]([CH3:25])[CH3:22])=[CH:15][C:10]=3[CH2:9]2)=[O:7])=[CH:20][CH:21]=1
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1)C2
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1)C2

Procedure:
A suspension of 3.1 g of crude 6-(p-chlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 30 cc of acetone is heated on a water bath for 1 hour. The title compound has a M.P. of 221°-223° (decomp., from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]=1>C(OCC)(=O)C.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]=2)=[C:2]([Cl:1])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc(NCCCO)n2)c(Cl)c1
Yield: 56.2 %

Procedure:
A solution of 1.00 g (3.08 mmol) 3-[4-(2-chloro-4-nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in a mixture of 30 ml ethyl acetate was hydrogenated over 200 mg palladium on barium sulphate for 10 h. The catalyst was filtered off and the filtrate evaporated. The obtained oil was dissolved in ethyl acetate and purified by chromatography on silica (ethyl acetate) to give 510 mg (56%) of 3-[4-(4-amino-2-chloro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol as colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[Cl:15].[Li+].[BH4-].CO.[OH-].[Na+]>CCOCC>[Cl:15][C:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10][C:6]=1[CH2:5][CH2:4][CH2:3][OH:2]
Reactant: COC(=O)CCc1sc2ccccc2c1Cl
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: OCCCc1sc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
An ice cold solution of 3.63 g (14.3 mmol) of 15 in 60 mL of ether was treated with LiBH4 (621 mg, 28.5 mmol) and methanol (2 mL). After 30 min., 30 mL of 0.5 M NaOH solution was added. The mixture was extracted with ethyl acetate (2×25 mL) and the combined ethyl acetate solution washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (5-20% ethyl acetate/hexane) to give 2.57 g (11.3 mmol, 79%) of the alcohol (16).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1.S(OC)(O[CH3:21])(=O)=O>[OH-].[Na+]>[CH3:21][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCCC(c2cccc(O)c2)C1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C2CCCCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
Hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (21.9 g) was dissolved in 2 M sodium hydroxide solution (100 ml) and dimethyl sulphate (18.3 g, 14.5 ml) added. The reaction mixture was stirred at room temperature for 10 minutes then seeded. The product crystallised after leaving at 0° C. for 3 hours. The product was filtered, washed with water and dried affording 16.99 g of title compound as off-white powder m.p. 73°-74° C., identical to that obtained in Example 2.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:27][NH2:28]>>[NH:27]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:28]
Reactant: NN
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: NNc1cc2c(nn1)CCN(Cc1ccc(-c3ccccc3)cc1)C2

Procedure:
9.0 g of 3-chloro-6-(p-phenylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 55 cc of hydrazine hydrate and stirred at a bath temperature of 100° for 51/2 hours. After cooling the mixture with ice the title compound precipitates and is recrystallized from 200 cc of dimethyl formamide. M.P. 241°-244° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH3:25])[CH2:17][C:16]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([O:22]C)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>Br>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH3:25])[CH2:17][C:16]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([OH:22])[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)cc2c1OC(C)(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: Br
Product: Cc1ccc(S(=O)(=O)OCC2(C)Cc3cc(Cl)cc(O)c3O2)cc1
Yield: 88.1 %

Procedure:
Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (13.80 g, 0.036 mol) with hydrogen bromide (200 mL, 30 wt. % in acetic acid) generally according to the procedure described for Intermediate 46 afforded 11.7 g (80%) of (±)-(5-chloro-7-hydroxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 135-137° C.; Anal. calcd. for C17H17ClO5S: C, 55.36; H, 4.65. Found: C, 54.35; H, 4.52.
Reaction SMILES: Cl[CH:2]1[C:6]2=[N:7][C:8]3[N:9]([CH2:21][CH3:22])[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[O:4][CH2:3]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[CH2:21]([N:9]1[C:8]2[N:7]=[C:6]3[CH:2]=[CH:3][O:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]1)[CH3:22]
Reactant: CCOC(=O)c1cn(CC)c2nc3c(cc2c1=O)OCC3Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(CC)c2nc3ccoc3cc2c1=O
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 3.2 g of ethyl 3-chloro-5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro[3,2-b]-1,8-naphthyridine-7-carboxylate (Compound XII where R1 =R3 =C2H5, X=Cl) dissolved in 50 ml of dimethylformamide, 3.2 g of 1,8-diazabicyclo[5,4,0]-7-undecene was slowly added dropwise and the mixture was stirred at 40° to 45° C. for 1 hour. After removal of the solvent, the residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The chloroform layer separated out was washed with water, dried and evaporated in vacuo to obtain 2.3 g of ethyl 5,8-dihydro-5-ethyl-8-oxofuro[3,2-b]-1,8-naphthyridine-7-carboxylate.