Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:25][CH2:24]1.Cl>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (200 mg, 0.61 mmol) and 3-(4-methyl-1-piperazinyl)aniline (117 mg, 0.61 mmol) were combined in a vessel with 8 mL isopropanol and 12N HCl (51 μL, 0.61 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with diethyl ether to give 120 mg (40%) of an off-white solid as the HCl salt. Mass (M+H)+=480, 481, 482.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[NH:19][N:18]=[N:17][N:16]=1.C(N(CC)CC)C.Cl[CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[N:19]([CH2:28][C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[N:18]=[N:17][N:16]=1
Reactant: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Reactant: Cn1ccnc1CCl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(-c3nnnn3Cc3nccn3C)c2cc1OC
Temperature: 27.5 °C
Reaction time: 0.29 h
Yield: 35.2 %

Procedure:
Experimental Procedure: 50.0 ml of N,N-dimethyl acetamide and 5.0 g (0.019 mol) of 6,7-dimethoxy-4-(1H-tetrazol-5-yl)quinazoline were charged into a 250 ml of 4necked round bottom flask, connected to a mechanical stirrer, thermometer socket, condenser and addition flask under mild nitrogen atmosphere. 3.80 g (0.038 mol) of triethyl amine was added at 25-30° C. Stirred the mass for 15-20 min at 25-30° C. Reaction mass temperature was raised to 50-55° C. Maintained the mass temperature at 50-55° C. for 15-20 min. 2-chloro methyl -1-methyl-imidazole solution [2.50 g (0.019 mol) 2-chloro methyl -1-methyl-imidazole was dissolved in 25.0 ml of N,N-dimethyl acetamide] was added slowly at 50-55° C. for 30-45 min. Maintained the mass temperature at 50-55° C. for 15-20 min. Raised the mass temperature to 80-85° C. Maintained the mass temperature at 80-85° C. for 7-8 hours. N,N-dimethyl acetamide was completely distilled under vacuum. Crude compound was purified by the column chromatography by using hexane and ethyl acetate. Obtained pure compound weight 2.40 g (yield 35.2% by theory).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:2])[O:3]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21
Temperature: 15 °C

Procedure:
As taught by U.S. Pat. No. 3,860,579, recrystallized phthalide (50 g., 0.375 mol) and recrystallized N-bromosuccinimide (0.375 mol) were refluxed 4.5 hours in the presence of about 100 mgm α-azobutyronitrile in one liter CCl4. The mixture was cooled to about 15° C. and filtered to remove succinimide which was itself washed with about 100 ml. CCl4 and filtered. The combined CCl4 phases were concentrated in vacuo to about 150 ml. giving solid 3-bromophthalide which was collected by filtration, washed with about 50 ml. CCl4 and air-dried to yield 54 g. which weighed 50 g. after recrystallization from boiling cyclohexane, m.p. 84°-86° C. ##STR39##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:10]=2[F:9])[N:3]=[CH:4][N:5]=1
Reactant: Nc1cccc(F)c1F
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Product: Fc1cccc(Nc2cc(Cl)ncn2)c1F
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To 14 ml of ethanol were added 2.2 g of 4,6-dichloropyrimidine and 2.3 g of 2,3-difluoroaniline, followed by heating under reflux for 6 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 3.5 g of 4-chloro-6-(2,3-difluoroanilino)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([NH:8][C:9]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1NC(=S)N(C)OCC(=O)O
Yield: 97.8 %

Procedure:
A mixture of 5-chloro-2-methoxyphenyl-isothiocyanate (11.45 g), N-methyl aminooxy acetic acid hydrochloride (8.15 g), triethylamine (20 g) and chloroform (250 mL) was heated at reflux for three hours, then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give (17.1 g) of [[[[(5-chloro-2-metoxyphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil that solidifies upon standing. The acid (15.2 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (10.4 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (40-60% methylene chloride in hexane). The title compound (5.1 g) was obtained as a solid, m.p. 189-191° C. Mass spectrum (El, M.+) m/z 286/288. 1H-NMR (DMSO-d6; 400 MHz) δ7.44 (d, 1H), 7.31 (s, 1H), 7.14 (d, 1H), 5.06 (s, 2H), 3.73 (s, 3H), and 3.63 ppm (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COCCN
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: COCCNC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2-methoxyethanamine (19 μl, 0.23 mmol) via procedure W to afford 50 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)carbamimidoyl)benzamide. MS (Q1) 409 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].CS(O[CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:22]([CH2:21][CH2:20][N:10]1[CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12][CH2:11]1)=[N+:23]=[N-:24]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: [N-]=[N+]=NCCN1CCc2ccc([N+](=O)[O-])cc2CC1

Procedure:
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (1.1 g), 2-methanesulphonyloxyethyl azide (0.92 g) and potassium carbonate (0.76 g) were heated under reflux in acetonitrile for 18 hours. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate then washed three times with aqueous sodium carbonate and three times with brine. The organic layer was dried, filtered and evaporated in vacuo to give an oil which was purified by chromatography on silica eluting with ethyl acetate/hexane (1:1). The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.65 g, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]([OH:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[C:3]([CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccnc1C(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccnc1C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A solution of 1-(3-methyl-pyridin-2-yl)-ethanol (330 mg, 2.41 mmol) (Kawasaki et al. Nippon Kagaku Zasshi 1962, 83, 949) and NEt3 (0.50 mL, 3.6 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. under N2. MsCl (0.22 mL, 2.8 mmol) was added and the reaction was stirred at 0° C. for 15 minutes. The reaction was diluted with saturated aqueous NaHCO3 (10 mL), the layers were separated and the aqueous solution was extracted with CH2Cl2 (10 mL×2). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure, giving the crude methanesulfonic acid 1-(3-methyl-pyridin-2-yl)-ethyl ester as an orange oil (484 mg, 2.25 mmol, 93%). 1H NMR (CDCl3) δ 1.76 (d, 3H, J=6.6 Hz), 2.45 (s, 3H), 2.84 (s, 3H), 6.07 (q, 1H, J=6.6 Hz), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (dd, 1H, J=7.8, 0.9 Hz), 8.51 (dd, 1H, J=4.8, 0.9 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:9]=3[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CN1C(=O)CCC1>[N:15]1([C:2]2[C:3]3[C:10]4[CH:11]=[CH:12][N:13]=[CH:14][C:9]=4[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: Clc1ncnc2[nH]c3cnccc3c12
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: c1cc2c(cn1)[nH]c1ncnc(N3CCOCC3)c12
Yield: 33.1 %

Procedure:
A mixture of 4-chloro-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidine (18 mg, 0.09 mmol), morpholine (23 μL, 0.26 mmol) and triethylamine (62 μL, 0.44 mmol) in 1 mL of NMP was irradiated in a microwave reactor at 150° C. for 20 minutes. The reaction mixture was evaporated to dryness and the residue purified by prep HPLC to give 7.6 mg of a white solid. 1H NMR (DMSO, 6, ppm) δ 3.65-3.75 (8H, m), 7.70 (1H, d, J=5.5 Hz), 8.45 (1H, d, J=5.5 Hz), 8.55 (1H, s), 8.85 (1H, s), 12.50 (1H, br s); LC-MS (2) Rt 1.46 min; m/z (ES+) 256.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=[C:28]([NH2:41])[N:27]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:31]4[C:26]([CH3:25])=[N:27][C:28]([NH2:41])=[N:29][CH:30]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: Cc1nc(N)ncc1-c1ccc2c(c1)-c1nc(C(=O)N(CCO)C(C)C)sc1CCO2
Yield: 1.1 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.2 mg, 0.127 mmol) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (35.8 mg, 0.152 mmol) were reacted to give 278 (0.6 mg, 1% yield M+1 440.1)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:36]([NH:39][CH:19]1[CH2:20][N:15]([C:13]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:14])[CH:16]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:17][CH2:18]1)([CH3:38])[CH3:37]
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Reactant: CC(C)N
Product: Cc1nc(-c2ccccc2)c(C(=O)N2CC(NC(C)C)CCC2CNC(=O)c2cccc3cccnc23)s1

Procedure:
N-((5-(Isopropylamino)-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and isopropyl amine. (ESI) 528 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[CH:10]([NH:13][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:12])[CH3:11]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)N
Product: CC(C)Nc1cc(Cl)nc(Cl)n1

Procedure:
400 (2.18 mols) of 2,4,6-trichloro-pyrimidine are dissolved in 2000 cc of alcohol. 280 g (4.75 mols) of isopropyl amine in 200 cc of alcohol are added to the solution while stirring and cooling, the temperature being maintained below 30°. The mixture is subsequently stirred at room temperature for a further 60 minutes and the alcohol is then removed by evaporation in a water jet vacuum until the mixture hardens to a solid mass. The solid residue is washed with water and subjected to steam distillation. This distillation is continued until only traces of the steam-volatile 2-isopropylamino-4,6-dichloro-pyrimidine are deposited in the receiver. The steam-nonvolatile 4-isopropylamino-2,6-dichloro-pyrimidine is obtained. After distillation in a vacuum (B.P. 124°/0.1 mm of Hg) the pure product, having a M.P. of 69°-70° after recrystallization from water/alcohol, is obtained.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14]Br.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[CH2:14][C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[CH:6]=3)[C:3]2=[O:16])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(OC)c(OC)cc1CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)N(c1ccc(Cl)cc1)C2

Procedure:
A solution of 2-bromomethyl-4,5-dimethoxy-benzoic acid methyl ester (2.9 g), 4-chloroaniline (1.28 g) and triethylamine (1.4 ml) was refluxed in toluene for six hours. The reaction mixture was stirred in an ice bath, filtered and washed with 1 M hydrochloric acid and water.
Reaction SMILES: [OH-].[K+].O.[C:4]1([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([CH2:10][O:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:19]2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (15° C.) mixture of 11.1 parts of potassium hydroxide and 96 parts of water wa added dropwise a solution of 31.8 parts of ethyl 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoate in 38 parts of ethanol during 20 minutes. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was evaporated at <50° C. The reaction mixture was poured into crushed ice and treated with concentrated hydrochloric acid. The separated aqueous layer was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 29 parts (100%) of 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoic acid as a residue (int. 33).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3): δ 1.19 (s, 3H), 1.20 (s, 3H), 4.354.38 (m, 1H), 6.63 (d, J=9.2 Hz, 2H), 7.24 (m, 2H), 7.35-7.38 (m, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.70-7.73 (m, 1H), 8.51 (bs, 1H), 8.68 (bs, 1H), MS: M/z=431.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([SH:37])([C:33]([F:36])([F:35])[F:34])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[OH-].[K+].[NH2:40]OS(O)(=O)=O>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:33]([F:34])([F:36])[F:35])[S:37][NH:40][C:12]([C:14]3[CH:15]=[C:16]4[CH2:17][O:18][C:19]5([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]5)[C:20]4=[CH:21][CH:22]=3)([OH:13])[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(S)(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3(O)CC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)SN3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of Intermediate 6 (530 mg) in a solution of potassium hydroxide (182 mg) in water (9 mL) was added a solution of hydroxylamine-O-sulfonic acid (183 mg, 2 eq) in a solution of potassium hydroxide (273 mg) in water (18 mL) and the resulting mixture was stirred at room temperature for 30 min under nitrogen. The mixture was diluted with ethyl acetate and washed with brine. The organic extract was concentrated and subjected to silica gel column chromatography (0 to 30% ethyl acetate in heptane) to yield 150 mg of Intermediate 7 as a mixture of diastereomers.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[CH:16]1([O:15][C:14]2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=[C:6]3[C:5]=2[NH:4][C:1](=[O:3])[CH:2]=[C:7]3[OH:8])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(O)cc(=O)[nH]c2c1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (6.42 g, 20.9 mmol) and anhydrous tetrahydrofuran (THF) (60 mL) was added via syringe pump (1 mL/min) to a solution of potassium bis(trimethylsilyl)amide (KHMDS) (150 mL, 0.5M PhMe, 75 mmol) at −78° C. under N2. The reaction was allowed to slowly warm to room temperature as the bath expired overnight. After 17, h, the reaction was poured into ice/water (250 mL), let stir for 10 min, and the layers were separated. The aqueous was washed with ether (150 mL), acidified with conc. HCl (7 mL), and filtered to give 8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one: MS (ESI): 276.0.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CCCCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using n-butyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as a viscous brown liquid. 1H NMR (CDCl3, 300 Mhz) δ 0.95 (t, 3H), 1.30–1.45 (m, 2H), 1.50–1.65 (m, 2H), 1.95–2.15 (m, 2H), 2.65–2.80 (m, 2H), 2.65–2.80 (m, 2H), 2.85–3.08 (m, 1H), 3.08–3.22 (m, 3H), 3.22–3.40 (m, 6H), 3.68–3.78 (m, 1H), 6.38 (d, J=7.1 Hz), 6.46 (d, J=7.1 Hz, 1H), 6.66 (t, J=7.7 Hz, 1H) ppm. MS (CI): 436 (M+H+).
Reaction SMILES: [H-].[Na+].[CH:3]([C:11]1[N:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:14][CH:15]=1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:21](OC)=[O:22].C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:22][CH:21]=[C:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC=O
Reactant: COC(=O)Cn1cccc1C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)n1cccc1/C=C/c1ccccc1
Yield: 112.5 %

Procedure:
Sodium hydride (0.63 g, 0.013 mol) was washed with petrol 60°-80° and suspended in DMF (30 ml) under nitrogen. To this methyl (2-styrylpyrrol-1-yl)acetate (1.6 g, 0.0066 mol) and methyl formate (8.2 ml, 0.13 mol) in DMF (10 ml) was added dropwise at room temperature. After 4 hours it was poured into 200 ml of saturated sodium bicarbonate, extracted with diethyl ether (2×100 ml), then the aqueous layer was neutralised with concentrated hydrochloric acid and extracted again with diethyl ether (2'100 ml). This was washed with brine, dried and evaporated to give methyl 3-hydroxy-2-[(E)-2-styrylpyrrol-1-yl]acrylate (2.0 g) as an orange-yellow oil. This was used in the following reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[CH:19]=1>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:20]4[CH:19]=[C:18]([CH3:17])[CH:23]=[CH:22][N:21]=4)=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)c1
Temperature: 120 °C
Yield: 87.2 %

Procedure:
A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.512 mmol), 4-methyl-2-tributylstannanylpyridine (235 mg, 0.614 mmol), Pd2(PPh3)2Cl2 (36 mg, 0.051 mmol) and copper iodide (29 mg, 0.153 mmol) in DMF (4 mL) was purged with nitrogen and then heated at 120° C. for 45 min using microwave irradiation. The reaction mixture was diluted with MeOH (30 mL) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by Si-PCC, gradient 0-3% MeOH in EtOAc) affording 9-Bromo-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (159 mg, 87%). LCMS: RT 2.44 min [M+H]+ 355.9/357.8