Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:7][CH:6]=1.S(OC)(O[CH3:25])(=O)=O.O>[OH-].[Na+]>[CH3:25][O:12][CH2:11][CH:10]([O:9][C:8]1[CH:14]=[CH:15][C:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:13]
Reactant: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
6 g of β-[4-(2,4-dichlorophenoxy)phenoxy]propanol was dissolved in 3.4 g of 30% aqueous sodium hydroxide. The solution was heated at a temperature of 60° C, then 3.1 g of dimethyl sulfate was added dropwise to the solution with stirring and the mixture was allowed to react for 1.5 hours. The reaction mixture was poured into an appropriate amount of water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate, and the ether was removed by distillation. The residue was distilled under reduced pressure to obtain 3.0 g of the desired product having a boiling point of 182° to 185° C/1.5 mmHg.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[C:22]1([CH2:28][CH2:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>C(O)C>[C:22]1([CH2:28][CH2:29][CH:30]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1SC(=CCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 1.34 g (10 mmol) of 3-phenylpropionaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/4) to yield 2.27 g (quant, brown oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH2:14][O:15]C(=O)C)=[O:13])[NH:7][C:6](=[O:19])[CH2:5]2.O.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[CH2:14][OH:15])[NH:7][C:6](=[O:19])[CH2:5]2
Reactant: CC(=O)OCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Yield: 93.3 %

Procedure:
Acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 27a (58 mg, 0.22 mmol) was dissolved in 1 ml of methanol under stirring, and added with 1 ml of water and sodium hydroxide (15 mg, 0.375 mmol) to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred for another 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The resulting solid was washed with water for three times and dried to obtain the title compound N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 27b (46 mg, yield 93.8%) as a gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=O)[CH:15]=[CH:16]N(C)C)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]([F:33])([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](=[NH:27])[NH2:26].CC(C)([O-])C.[K+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[CH:16][N:26]=[C:25]([C:24]3[C:23]([C:22]([F:32])([F:21])[F:33])=[N:31][CH:30]=[CH:29][CH:28]=3)[N:27]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: N=C(N)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)C=CN(C)C)cc([N+](=O)[O-])c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2ccnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 80 °C

Procedure:
A stirred suspension of 1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-propen-1-one (0.28 g, 1.0 mmol), 2-(trifluoromethyl)nicotinimidamide (0.283 g, 1.5 mmol) and potassium tert-butoxide (0.17 g, 1.5 mmol) in absolute ethanol (5 mL) was heated to 80° C. in a sealed tube for one hour and then allowed to cool to room temperature. The mixture was poured onto cold water (100 mL) and the resulting precipitate was filtered off, washed with water and dried to give 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)pyrimidine, 0.296 g (73%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].Cl[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:12]#[N:13].O>COCCOC>[NH2:13][C:12]1[CH:11]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:5][C:4]=1[C:3]([O:7][CH3:8])=[O:6]
Reactant: CC(C)(C)C(Cl)=CC#N
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1oc(C(C)(C)C)cc1N
Temperature: 85 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a slurry of NaH (5.98 g, 0.24 mol, 2.6 equiv) in anh. DME (800 mL) at 0° C. was added methyl glycolate (23.0 g, 0.26 mol, 2.8 equiv) over 20 min. The mixture was stirred for 1 h at room temp. and a solution of 3-chloro-4,4-dimethyl-2-pentenenitrile (13.1 g, 0.091 mol) in DME (100 mL) was added. The resulting solution was heated to 85° C. for 42 h, cooled to room temp., and treated with H2O (100 mL). The resulting mixture was separated between H2O (200 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The residual oil was purified by flash chromatography (300 g SiO2, gradient from 50% CH2Cl2/hexane to 20% EtOAc/CH2Cl2) to give methyl 3-amino-5-tert-butylfuran-2-carboxylate as a yellow solid (2.98 g, 17%): mp 91-2° C.; TLC (20% EtOAc/hexane) Rf0.36; 1H NMR (CDCl3) δ1.26 (s, 9H), 3.84 (s, 3H), 4.54 (br s, 2H), 5.75 (s, 1H); 13C NMR (CDCl3) δ28.5 (3C), 33.0, 50.7, 98.5, 128.8, 131.0, 160.7, 168.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:21]=[CH:20]C(C#N)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([OH:26])(=[O:25])[CH3:24]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:21]=[CH:20][C:24]([C:23]([OH:26])=[O:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 38 %

Procedure:
4-(4-Benzylpiperazin-1-yl) benzonitrile (4.0 g, 15 mmol) was dissolved in glacial acetic acid (40 mL), 6 M hydrochloric acid (50 mL) was added and the reaction mixture was stirred at 100° C. for 17 h. The solvent was evaporated, the residue was suspended in water (10 mL) and the pH was adjusted to 3 by addition of 2 M sodium hydroxide (35 ml). The slurry was stirred at 50° C. for 2 h, cooled and the precipitate was filtered and dried in vacuo to give 4.1 g of a crude product. The solid was partitioned between methylene chloride (40 mL) and water (220 mL) with 2 M sodium hydroxide (8 mL). The aqueous phase was washed with methylene chloride (40 mL) and the pH was adjusted to 5 with 2 M hydrochloric acid. The aqueous phase was cooled, the precipitate was filtered and dried in vacuo to give 1.6 g (38% yield) of the title compound: mp 226° C. (dec); EIMS (70 eV) m/z (relative intensity) 296 (44, M+).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[Cl:1][CH2:2][CH:3]=[N:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CCCl
Reactant: NCc1ccccc1
Solvent: O
Product: ClCC=NCc1ccccc1

Procedure:
A solution of 4 ml of chloroacetaldehyde in 20 ml of demineralized water was cooled and a solution of 2.14 g of benzylamine in 10 ml of water was added thereto with stirring. After stirring for 5 minutes at 10° to 15° C., a gum was obtained and a turbid solution which was extracted with 30 ml and then with 20 ml of benzene. The organic solution was dried, filtered, rinsed and the filtrate was evaporated to dryness under vacuum to obtain 3.34 g of 2-chloro-N-benzylethanimine which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=1.C([O-])(=O)C.[K+]>CCO.O>[F:1][C:2]1[C:7]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=2)=[CH:6][C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1
Reactant: COCCOc1cnc(F)c(B(O)O)c1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
To a 20 mL microwave reaction tube was added 2-fluoro-5-(2-methoxyethoxy)pyridin-3-ylboronic acid (1.06 g, 4.95 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 0.508 g, 3.51 mmol), Am-Phos (Aldrich, 0.125 g, 0.176 mmol) and potassium acetate (Aldrich, 1.04 g, 10.6 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and 10% IPA in CHCl3 (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was treated with DCM and the resulting solid was collected to afford 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.234 g) as an off-white solid. The filtrate was concentrated and purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 12.5%) to afford additional material (0.399 g) as a pale yellow solid. Total yield was 0.632 g, 64%. 1H NMR (400 MHz,CDCl3) δ ppm 8.14 (dd, J=7.63, 3.13 Hz, 1H) 8.01 (dd, J=2.93, 1.76 Hz, 1H) 5.56 (br. s., 2H) 4.19-4.27 (m, 2H) 3.75-3.81 (m, 2H) 3.46 (s, 3H) 2.53 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15]C)[C:13]=1[OH:14])[CH:9]=[O:10].N1C=CC=CC=1.Cl>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([OH:15])[C:13]=1[OH:14])[CH:9]=[O:10]
Reactant: COc1cc(C=O)cc(F)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(F)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
Anhydrous aluminum chloride (1.11 g, 8.2 mmol) was added to a solution of 3-fluoro-4-hydroxy-5-methoxy benzaldehyde (1.2 g; 6.8 mmol) in dry dichloromethane (16 ml) under an atmosphere of nitrogen. The reaction mixture was cooled down to 0° C., pyridine (2.5 ml; 31 mmol) was slowly added and the solution was heated to reflux and stirred for 24 h. The solution was cooled to 0° C. and 4M aqueous hydrochloric acid was added to the mixture until the pH was approximately 2. The organic phase was discarded and the water phase was extracted with ethyl ether (3×15 ml). The organic extracts were combined then dried over sodium sulfate and concentrated under vacuum to give 3-fluoro-4,5-dihydroxybenzaldehyde (0.904 g; 85% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 9.68 (d, 1H), 7.17 (dd, 1H), 7.16 (br. s, 1H). MS (EI) for C7H5FO3: 157 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([OH:22])=O)=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.Cl.[F:26][CH:27]1[CH2:30][NH:29][CH2:28]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:29]3[CH2:30][CH:27]([F:26])[CH2:28]3)=[O:22])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: FC1CNC1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), 3-fluoroazetidine hydrochloride (152 mg, 1.37 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (398 μl, 2.28 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at room temperature under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution; the precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamide (158 mg, 89.8%) as a white solid. Mp.: 243-4° C. MS: m/z=387.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][CH:11]1[CH:18]2[CH2:19][C:14]3([C:21]([NH2:23])=[O:22])[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]3)[CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:10][CH:11]2[CH:12]3[CH2:20][CH:16]4[CH2:15][C:14]([C:21](=[O:22])[NH2:23])([CH2:19][CH:18]2[CH2:17]4)[CH2:13]3)=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)C12CC3CC(C1)C(N)C(C3)C2
Reactant: O=C(O)c1ccc(Br)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C12CC3CC(C1)C(NC(=O)c1ccc(Br)o1)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution prepared by dissolving 100 mg of 5-bromofuran-2-carboxylic acid, 145 mg of (E) type 4-aminoadamantane-1-carboxylic acid amide (prepared from Preparation Example 1), and 202 mg of TBTU in MC was added dropwise 0.2 mL of DIEA and then stirred at room temperature for 4 hours. The reaction solution was washed with a 1N solution of HCl and a 1N solution of NaOH, respectively, and then washed again with brine. The resulting organic solution was dried over MgSO4 and after filtration, was distilled under a reduced pressure. The compound thus obtained was purified via recrystallization by using MeOH and ether to produce 150 mg of a white solid product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl[C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[C:15]=1[C:16]([OH:18])=[O:17].[OH-].[Na+].C(Cl)(Cl)Cl>CN(C)C1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:14]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCOc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A solution of 25 g of p-butoxyaniline and 17.85 g of 2,6-dichloro-3-nitrobenzoic acid in 50 ml of N,N-dimethylaniline was heated under nitrogen at 100° for 18 hours. The reaction mixture was treated with 500 ml of 0.2N sodium hydroxide and 500 ml of chloroform. The aqueous layer was washed with additional chloroform and acidified to provide 2-[(4-butoxyphenyl)amino]-6-chloro-3-nitrobenzoic acid, mp 166°-169° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: N
Product: Fc1cccc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3-fluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.45-7.53 (m, 1H), 7.69 (td, J=8.1, 5.6 Hz, 1H), 8.00 (ddd, J=9.1, 2.6, 1.4 Hz, 1H), 8.11 (dt, J=7.9, 1.2 Hz, 1H), 8.39 (dd, J=5.4, 2.2 Hz, 1H), 9.45 (dd, J=5.2, 1.2 Hz, 1H), 9.87 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z=243 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:13][S:14]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2](=[O:12])[NH:1]2)(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Product: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6-Chlorosulfonyl-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Keana et al. (J. Org. Chem. 48: 3654 (1983)). To 1,4-dihydro-2,3-quinoxalinedione (1.0 g, 6.2 mmol) was added all at once 3.0 mL of chlorosulfonic acid. The mixture was stirred under N2 at 60° C. for 2 h, allowed to come to room temperature and the solution added slowly dropwise to 25 mL of crushed ice. The resulting solid was vacuum filtered and rinsed with ice/H2O. The white solid was further dried at 0.5 torr (25° C.) over CaSO4 to yield 1.1 g (68%). 1H NMR (d6 -DMSO) δ 7.07 (d, J7-8 =8.1, 1H, H8), 7.29 (dd, J7-8 =8.1, J6-7 =1.0, 1H, H7), 7.40 (d, J5-7 =1.0, 1H, H5). EIMS m/z262 (M+2, 15), 260 (M+, 40), 225 (35), 105 (43), 36 (100, bp). EIHRMS calc. for C8H5ClN2O4S 259.9687, found 259.9645.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17].[H-].[Na+]>CN(C=O)C>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=[O:14])[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-tert-butyloxycarbonyl-2-piperazinone (10 g, 50 mmol) and allyl bromide (7.25 g, 60 mmol) in DMF (75 mL) at 0° C. was added sodium hydride (2.4 g of a 60% suspension in mineral oil, 60 mmol) in portions over a period of 10 min. The mixture was allowed to warm to ambient temperature and stirred for 18 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography using a gradient elution of 33%, 40%, 50%, 60% EtOAc in hexanes. Concentration of product-containing fractions in vacuo gave the title compound as an oil. HPLC RT=2.80 min (Method A), ES MS (M+H)=241, 1H NMR (400 MHz, CDCl3) δ 5.76 (ddt, 1H), 5.2 (overlapping doublets, 2H), 4.10 (s, 2H), 4.04 (d, J=6 Hz, 2H), 3.64 (t, J=7 Hz, 2 H), 3.50 (t, J=7 Hz, 2H), 1.47, (s, 9H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:9][O:8][CH2:7][C:5]1[O:6][C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COCc1oc(Br)cc1C(=O)OC
Reactant: OB(O)c1ccccc1
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: COCCOC
Solvent: O
Product: COCc1oc(-c2ccccc2)cc1C(=O)OC
Yield: 87.5 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)-3-furancarboxylate (3.7 g), phenylboronic acid (2.2 g), tetrakis(triphenylphosphine)palladium(0) (0.9 g), 2N aqueous sodium carbonate solution (18 mL) and 1,2-dimethoxyethane (30 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (3.2 g, 87%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1.Cl>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:22][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: OCC1CC1
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Temperature: 80 °C
Reaction time: 25 h
Yield: 57.2 %

Procedure:
To a solution of 5-chloro-4-iodo-pyridine-2-carboxylic acid (CAN 120643-06-3, 600 mg, 2.12 mmol) in THF (20 mL) and DMF (2 mL) was added with stirring potassium tert-butoxide (1.0 g, 8.91 mmol) and cyclopropanemethanol (1.5 mL, 18.8 mmol). The resulting mixture was stirred at 80° C. for 25 h, cooled, acidified with hydrochloric acid (25 mL, 1 N) and partitioned into ethyl acetate. The organic portions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by prep. HPLC (Gemini NX, acetonitrile/water gradient) to give the title compound (276 mg, 57%) as light yellow solid. MS (ESI, m/z): 228.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:33]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:31])([CH3:32])[CH:28]([CH3:29])[CH3:30])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14]([Br:33])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Yield: 100 %

Procedure:
To a solution of 22.78 g (4R,9aR)-6-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 200 ml tetrahydrofuran was added at 0° C. 8.78 g (0.049 mol) N-bromosuccinimide and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with 500 ml ethyl acetate and extracted sequentially with a 10% aqueous solution of sodium thiosulfate, a 10% aqueous solution of citric acid, water and brine dried over sodium sulfate, evaporated under aspirator vacuum and dried to constant weight under high vacuum to yield 26.5 g of the title compound as colorless oil. (MS: 541 (M+H+)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:16]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][C:13]2([C:9]3=[N:10][CH:11]=[CH:12][N:8]3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:26]2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccn2-c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1ccnc12
Yield: 50.3 %

Procedure:
tert-Butyl 4-[1-(2-fluorophenyl)imidazol-2-yl]-4-hydroxy-piperidine-1-carboxylate (294 mg, 0.81 mmol) and K2CO3 (337 mg, 2.44 mmol) were heated at 110° C. for 16 h in DMF (5 mL). The solvent was evaporated and the resulting material was partitioned between dichloromethane and water. The organics were separated and washed with brine, dried over sodium sulfate and evaporated. The crude material was purified by column chromatography (0-50% ethyl acetate in hexanes) to give tert-butyl spiro[imidazo[2,1-c][1,4]benzoxazine-4,4′-piperidine]-1′-carboxylate (139 mg, 50%). ESI-MS m/z calc. 341.2, found 342.3 (M+1)+. Retention time 1.31 minutes (3 min run).