Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A mixture of 2,4′-dibromoacetophenone (22.4 g) and 2-amino-4-picoline (8.68 g) in ethanol (80 mL) was heated at reflux temperature for 3 hours. The reaction mixture was cooled to ambient temperature and the crystalline solid isolated by filtration, washed with ethanol and dried in vacuo to give the title compound (13.1 g). Step B Preparation of 2-[4-[4-Hydroxybut-1-ynyl]phenyl]-7-methylimidazo[1,2-a]pyridine The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(O) (0.1 g), triethylamine (1.27 g), and Cul (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g). Step C Preparation of 2-[4-[4-Methanesulfonyloxybut-1-ynyl]phenyl]-7-methylimidazo[1,2-a]pyridine The product of Step B (0.135 g) in dichloromethane (3 mL) was treated with pyridine (0.37 g) and cooled to 10° C. The cold solution was treated with methanesulfonyl chloride (0.112 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with 1% H2SO4 solution, saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.115 g). Step D Preparation of 2-[4-[4-Piperidinobut-1-ynyl]phenyl]-7-methylimidazo[1,2-a]pyridine The product of Step C (1.00 g) in acetonitrile (15 mL) was treated with piperidine (0.269 g) and potassium carbonate (1.17 g) and heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature, washed with water (20 mL), dried over magnesium sulfate, filtered and evaporated to give crude product. Silica gel chromatography (methanol/dichloromethane) afforded the title compound (1.0 g). MS (ESI) m/z 344.1 (M+H+). 1H NMR (DMSO) δ 8.23 (d, J=6.95 Hz, 1 H), 8.15 (s, 1 H), 7.73 (d, J=8.37 Hz, 2 H), 7.25 (d, J=8.34 Hz, 2 H), 7.17 (s, 1 H), 6.58 (dd, J=6.9,1.45 Hz, 1 H), 2.33 (m, 6 H), 2.23 (b, 2 H), 2.18 (s, 3 H). 1.33 (pent, 4 H), 1.21 (pent, 2 H). HRMS: MH+ calcd for C23H26N3, 344.2127; found, 344.2134. Analysis: Calc'd for C23H25N3; C, 80.43; H, 7.34; N, 12.23. Found: C, 80.27; H, 7.15; N, 11.81.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc(COCc2ccc(F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.062 g) as a light yellow gum (0.087 g). MS (ESI−): 419.0. ([M−H]−)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:13]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:11]=1
Reactant: C1CCNCCNC1
Reactant: Cc1cc(C)c2oc(S)nc2c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2oc(N3CCCCNCC3)nc2c1
Yield: 171.8 %

Procedure:
5,7-Dimethyl-2-mercapto-benzoxazole (109 mg) was dissolved in toluene (6 ml), and the solution was mixed with 1,4-diazacyclooctane (1.93 g) which has been obtained in accordance with the method described in Carib. J. Sci., 14, 77 (1974) and then stirred with heating for 3 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=5:1) to obtain the title compound 5,7-dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole (271 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].[H-].[Na+].Cl>O.O1CCOCC1>[C:23]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16])#[N:24]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O

Procedure:
86.2 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 63.3 g of ethyl cyanoacetate are initially introduced into 1,000 ml of dioxane. 15.8 g of NaH are added in portions. The mixture is then heated to reflux for 4 hours. The completeness of the reaction is checked using thin-layer chromatography. After completion of the reaction, water is added dropwise. The mixture is then rendered acidic using dilute HCl and extracted using methylene chloride. The organic phase is dried and evaporated. The residue is recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:17][CH:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>O>[OH:17][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH:9]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16]
Reactant: c1c[nH]cn1
Reactant: Clc1ccccc1C1OC1c1ccccc1Cl
Solvent: O
Product: OC(c1ccccc1Cl)C(c1ccccc1Cl)n1ccnc1
Yield: 86.8 %

Procedure:
A mixture of 11 g (0.04 m) of 2,2'-dichloro-α,α'-epoxybibenzyl and 15 g (0.22 m) of imidazole is heated at 160° for 11/2 hours. The reaction is cooled, diluted with water, and extracted with ether. The combined ether extracts are washed with water, then saturated sodium chloride solution, and dried over MgSO4. Solvent is evaporated to give 12 g of a gummy solid, mp 62°-68°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=2)=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=3)[CH2:14][O:15][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1cc(-c2ccc(Cl)cc2F)c(CO)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc2c(cn1)COc1cc(Cl)ccc1-2
Temperature: 95 °C
Yield: 84 %

Procedure:
To a stirred solution of N-(4-(4-chloro-2-fluorophenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide (9 g, 23.82 mmol) in DMF (90 mL) was added potassium carbonate (9.88 g, 71.5 mmol) and the resultant mixture was sealed tightly and heated at 95° C. for 16 h. The reaction mixture was then cooled to room temperature and volatiles were removed under reduced pressure. The crude material was taken up in water (200 mL) and filtered. The residue was washed with water (2×250 mL) and dried under reduced pressure for 16 h to afford N-(8-chloro-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (5.5 g, 20.02 mmol, 84% yield) as a pale brown solid. LCMS (ESI) m/e 275.2 [(m)−, calcd for C14H12ClN2O2275.1] LC/MS retention time (method D): tR=1.77 min; 1H NMR (400 MHz, DMSO-d6) δ 10.6 (s, 1 H), 8.41 (s, 1 H), 8.25 (s, 1 H), 7.78 (d, J=8.4 Hz, 1 H), 7.22-7.15 (m, 2 H), 5.2 (s, 2 H), 2.2 (s, 3 H).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH2:13]([NH:20][C:10](=[O:11])[CH2:9][CH2:8][CH:7]([OH:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(c2ccccc2)O1
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: O=C(CCC(O)c1ccccc1)NCc1ccccc1
Yield: 71.5 %

Procedure:
A solution of γ-phenyl-γ-butyrolactone (5.17 g, 31.8 mmol) and benzylamine (3.48 ml, 31.8 mmol) in 200 ml of benzene was refluxed under a nitrogen atmosphere for 20 hours. An additional 1.75 ml (16.0 mmol) of benzylamine was added and the solution refluxed for 24 hours. When the reaction was partitioned with 1 N HCl a white solid precipitated. The solid was collected by filtration and dried to give N-benzyl-4-hydroxy-4-phenyl-butyramide (6.12 g, 72%) as a white solid, mp 92-94° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22](=[O:31])[CH:23]=[C:24]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25]1)[CH3:20].[N+:32]([CH3:35])([O-:34])=[O:33]>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1([CH2:35][N+:32]([O-:34])=[O:33])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25]1)[CH3:20]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCC(C)(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC(C)(C)C1
Temperature: 70 °C
Reaction time: 19 h
Yield: 40.8 %

Procedure:
Tetrabutylammonium fluoride (5.75 mL of a 1 M solution in THF, 5.75 mmol) was added to a solution of the ester 2 (697 mg, 3.83 mmol) and nitromethane (467 mg, 7.66 mmol) in THF (20 mL) and the mixture heated to 70° C. After 19 hours, nitromethane (233 mg, 1.9 mmol) and tetrabutylammonium fluoride (1.9 mL of a 1 M solution in TBF, 1.9 mmol) were added and reflux continued for 7 hours, whereupon the solution was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with 2N HCl (20 mL) then brine (20 mL). The organic phase was dried (MgSO4) and concentrated. The crude product was flash chromatographed (9:1 hexane/ethyl acetate) to give the nitro ester 3 (380 mg, 41%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(OC)c1

Procedure:
Using a Perrier modification, Perrier, Chem. Ber., Vol. 33, pp. 819 et seq. (1900), and Perrier, Bull. Soc. Chim. France, pp. 859 et seq. (1904), 1,3-dimethoxybenzene (138.0 g) (which may be obtained from Aldrich Chemical Company, Inc., Milwaukee, Wis.) is reacted with acetyl chloride (72.0 g), methylene chloride (500 ml), and aluminum chloride (145.0 g) to provide 2',4'-dimethoxy-acetophenone, which may then be purified using standard vacuum fractional distillation.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:17])[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.[OH-].[K+]>>[C:1]1(=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:17])=[CH:9][CH:10]=2)[C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(CC#N)cc1
Reactant: O=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(C(C#N)=C2CCCCC2)cc1
Yield: 62.4 %

Procedure:
The procedure outlined in example 1 is repeated with cyclohexanone (22.34 g, 0.29 mol), p-tolylacetonitrile (20.96 g, 0.16 mol) and KOH (1.79 g, 0.032 mol). Short path distillation of the crude at 0.05 mbar/115-130° C. followed by recrystallization from hexane yields 21.1 g (63% yield) of product as white crystals, m.p. 50.5-51.3° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:6](Br)[CH:5]=1.[CH2:17](OB(C=C)OCCCC)[CH2:18]CC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([CH:17]=[CH2:18])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:8]([F:10])[CH:9]=1
Reactant: C=CB(OCCCC)OCCCC
Reactant: COCOc1c(F)cc(C(=O)OC)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)cc(F)c1OCOC
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 3-bromo-5-fluoro-4-methoxymethoxybenzoic acid methyl ester (300 mg) and vinylboronic acid dibutyl ester (226 mg) in toluene (4 mL)-ethanol (2 mL) were added dichlorobis(triphenylphosphine)palladium (II) (36 mg) and an aqueous solution (1 mL) of sodium carbonate (217 mg). The mixture was stirred at 100° C. for 8 hours, and then allowed to stand for cooling down to room temperature. The resulting insoluble materials were filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1, v/v) to give the title compound (190 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]([N:13]([CH2:21][CH3:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[C:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])[CH3:34]>C1COCC1>[C:33]([C:36]1[CH:37]=[CH:38][C:39]([S:42]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:23])[CH3:1])[CH:4]=2)[CH2:10][C:11]([N:13]([CH2:21][CH3:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])(=[O:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(Cc1ccccn1)C(=O)CNc1cccc(N(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(Cc1ccccn1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)=O)cc1
Reaction time: 2 h
Yield: 36.4 %

Procedure:
A solution of 2-(3-dimethylamino-phenylamino)-N-ethyl-N-pyridin-2-ylmethyl-acetamide (2.50 mmol) and of DIPEA (5.00 mmol) in THF (10 mL) was added to a solution of 4-acetyl-benzenesulfonyl chloride (2.50 mmol) in THF (10 mL). The reaction mixture was stirred for 2 h, the solvents were removed and the residue was purified by preparative HPLC chromatography to give 451 mg (0.91 mmol, 36%) product as a brownish foam.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)=[O:30]>>[C:35]1([CH3:38])[CH:36]=[CH:37][C:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[CH:33][CH:34]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Product: Cc1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(CC4CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid p-tolyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using p-tolyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 544.2 [M]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C(O)C>[OH:21][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C:6]=1[C:4]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[S:31](=[O:32])(=[O:33])[N:34]=1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Solvent: CCO
Product: COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(CCC(C)C)c1=O)N2
Temperature: 180 °C
Yield: 45 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.040 g, 0.14 mmol) was mixed with 2-amino-5-methoxy-benzenesulfonamide (Example 2b, 0.0235 g, 0.14 mmol) and the resulting mixture was heated to 180° C. for 20 min. The resulting crude oil was allowed to cool to 25° C. and ethanol (0.5 mL) was added and sonicated to afford a tan precipitate, which was collected and dried in vacuo. The crude solid was dissolved in 1.0 M aqueous potassium hydroxide solution (0.5 mL) and heated to 110° C. for 12 h. The reaction mixture was allowed to cool to 25° C. and 10% aqueous hydrochloric acid solution (0.5 mL) was added and the resulting white precipitate was collected. The crude solid was washed with methanol and dried in vacuo to afford the desired product, 4-hydroxy-3-(7-methoxy-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.027 g, 0.063 mmol, 47% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (6H, d, J=6.4 Hz), 1.69 (1H, m), 1.78 (1H, m), 3.89 (3H, s), 4.39 (2H, t, J=7.6 Hz), 6.60 (1H, dd, J1=4.4 Hz, J2=2.8 Hz), 7.04 (1H, d, J=4.4 Hz), 7.05 (1H, dd, J1=4.8 Hz, J2=2.0 Hz), 7.25 (1H, m), 7.17 (1H, m), 7.39 (1H, d, J=2.0 Hz); LC-MS (ESI) calcd for C19H22N4O5S 430.49. found 431.33 [M+H+].
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]([CH3:13])([O-:12])[CH3:11].[K+]>O1CCCC1>[C:10]([O:12][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])([CH3:13])([CH3:11])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCC(=O)O1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCC(=O)O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
Glutaric anhydride (11.41 g.) was added portion-wise to a solution of potassium tert-butoxide (14.02 g.) in tetrahydrofuran (100 ml.) at ambient temperature. After the exothermic reaction was ceased, the reaction mixture was stirred at 40° C. for 15 minutes. Tetrahydrofuran was distilled off under reduced pressure. The residue was dissolved in water. After ethyl acetate was added, the solution was adjusted to pH 9 with aqueous potassium carbonate solution under ice-cooling. The separated water layer was washed with ethyl acetate, treated with activated charcoal, overlapped with ethyl acetate, and then adjusted to pH 4.0 with 10% hydrochloric acid under ice-cooling. The ethyl acetate layer was dried over magnesium sulfate, treated with activated charcoal, filtered and concentrated under reduced pressure to give glutaric acid mono-tert-butyl ester (10 g.).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([O:10][CH3:19])=[O:9])=[CH:13][CH:14]=1
Reactant: CO
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-(4-Bromophenoxy)-2-methylpropionic acid (1 g) was dissolved in methanol (5 mL), a catalytic amount of thionyl chloride was added, and the mixture was stirred at room temperature for 7 hrs. Saturated brine was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (920 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH3:2].[O:12]1CCOC[CH2:13]1>>[CH2:1]([N:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:10])[NH:11][C:13]1=[O:12])[CH3:2]
Reactant: C1COCCO1
Reactant: CCNc1c(N)ncnc1Cl
Product: CCn1c(=O)[nH]c2ncnc(Cl)c21
Yield: 60 %

Procedure:
A solution of N5-ethyl-6-chloropyrimidine-4,5-diamine (0.21 g, 1.22 mmol) and 1,1-carbonyldiimidazole (0.40 g, 2.44 mmol) in 1,4-dioxane (5 mL) was degassed, flushed with nitrogen and refluxed under nitrogen for 22 h. The solution was cooled and partitioned between ethyl acetate (15 mL), 1M hydrochloric acid (10 mL) and brine (5 mL). The organic layer was dried, filtered and concentrated to give 7-ethyl-6-chloro-7,9-dihydropurin-8-one (0.146 g, 0.735 mmol, 60%) as a yellow solid. LC-MS (LCT2) m/z 199, 201 [M+H+], Rt 4.62 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[NH2:10].O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[CH3:8][C:7]1[CH:6]=[C:5]([CH3:9])[CH:4]=[C:3]2[C:2]=1[NH:1][C:13](=[O:17])[C:14](=[O:15])[NH:10]2
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cc1cc(C)c2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 62.5 °C
Yield: 87.2 %

Procedure:
A mixture of 1,2-diamino-4,6-dimethylbenzene (424 mg, 3.11 mmole) and oxalic acid dihydrate (432 mg, 3.43 mmole, used as received) in 4N HCl (20 mL) was refluxed at 120-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the supernatant was removed. The yellow solid was washed with cold water (2×2 mL), collected by filtration, and dried in vacuo for 2 h, affording 516 mg of crude 5,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (87%) as a yellow powder. The crude product was taken up in 1 N NaOH (10 mL) and filtered. The filtrate was acidified to pH=3, affording the pure title compound (490 mg) as a light yellow powder; mp:345-347° C. (dec); IR (KBr, cm-1):3460, 3.190, 2986, 1716, 1709, 1630. 1H NMR (DMSO-d6): δ 11.858 (s, 1H), 11.173 (s, 1H), 6.766 (s, 1H), 6.745 (s, 1H), 2.280 (s, 3), 2.211 (s, 3). HRMS: calcd for C10H10N2O2 (M+) m/z: 190.0714; found: 190.0744.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][C:9](=O)[N:8]([CH2:13][CH2:14][CH3:15])[CH2:7]1)[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH3:15])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCOCC1CN(CCC)C(=O)CO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=CCOCC1CN(CCC)CCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-allyloxymethyl-4-n-propylmorpholin-5-one (65 g.) in dry ether (100 ml.) is added slowly with stirring to a suspension of lithium aluminium hydride (17.5 g.) in dry ether (700 ml.). The rate of addition is adjusted so that the reaction mixture refluxes gently. When the addition is complete the reaction mixture is stirred at ambient temperature (18°-20°C.) for 18 hours and then water (90 ml.) is added very carefully dropwise to decompose the complex and excess of lithium aluminium hydride. The ethereal solution is filtered and the solid residue is washed with ether. The filtrate and ethereal washings are combined, dried (Na2SO4), filtered and the ether evaporated. The product, 2-allyloxymethyl-4-n-propylmorpholine is obtained as an oil b.p. 80°-90°C. at 1 m.m. which forms a hydrogen oxalate, m.p. 125°-127°C.