Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:53]([NH:57][CH2:58][CH:59]([CH3:61])[CH3:60])[CH:54]([CH3:56])[CH3:55]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:22])[N:57]([CH2:58][CH:59]([CH3:61])[CH3:60])[CH2:53][CH:54]([CH3:56])[CH3:55])[CH:18]=2)[NH:13][C:12]=1[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CNCC(C)C
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid (200 mg in 12 mL methylene chloride) was added 104 mg 1-hydroxybenzotriazole followed by 118 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture stirred at room temperature. After 30 minutes, 0.35 mL of diisobutylamine was added and the mixture stirred at room temperature for 14 hours. The reaction was then concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) to give the title compound (230 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)([O-:24])(=[O:23])=[O:22].[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH2+:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1CCCNC1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O[C@H]1CCC[NH2+][C@H]1c1ccccc1

Procedure:
The mixture of cis- and trans-isomers of 3-hydroxy-2-phenylpiperidine (Example 2b) and 4-toluenesulfonic acid monohydrate was crystallized from methanol/ethyl acetate to give cis-3-hydroxy-2-phenylpiperidinium tosylate, m.p. 266°-267° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15](OC3C=CC=CC=3)[C:14]=2[N:13]=[C:12]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34].[OH-].[K+]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:34])[C:14]=2[N:13]=[C:12]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCc3ccccc3)c2c1C
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(N)c2nc(C)n(CCOCc3ccccc3)c2c1C
Temperature: 150 °C
Yield: 55 %

Procedure:
1-[2-(Benzyloxy)ethyl]-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (5.113 g, 13.195 mmol) from Part A and ammonium acetate (51 g) were combined in a dried glass pressure flask under nitrogen. The flask was sealed and heated to 150° C. for 46 hours. The reaction was complete, and the resulting solution was cooled and basified to a pH of about 12 with 1 N potassium hydroxide. The basic solution was extracted with dichloromethane (3×), and the organic layers were combined, washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether, and the resulting solids were filtered off. NMR analysis of the solids indicated residual phenol. The solids were dissolved in ethyl acetate. The ethyl acetate solution was washed with 1 N potassium hydroxide (4×), water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was diluted with diethyl ether, and after several hours the resulting crystals were filtered off and rinsed with diethyl ether. The resulting solids, which by NMR analysis were free of the phenol, were dried at 60° C. for 17 hours under high vacuum to provide 2.2515 g of 1-[2-(benzyloxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 136.8-137.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(Oc3ccc(N)nc3)ccn2)ccn1
Temperature: 80 °C
Yield: 88.7 %

Procedure:
A solution of Example A9 (0.440 g, 1.985 mmol) in dioxane (8 mL) was sparged with Ar, treated with a solution of K2CO3 (0.549 g, 3.97 mmol) in water (2 mL) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.565 g, 2.58 mmol), sparged again with Ar, treated with Pd(PPh3)4 (0.229 g, 0.199 mmol) and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine (490 mg, 89%) as a light brown solid. MS (ESI) m/z: 279.2 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(O[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)C#C.[O:38]1CC[CH2:40][CH2:39]1>O>[NH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:31]([O:30][C:24]1[CH:23]=[CH:28][CH:27]=[CH:26][C:25]=1[C:29]#[C:40][C:39](=[O:38])[CH2:2][C:1]([NH2:4])=[O:3])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C#CC(=O)Oc1cccc(C)c1OCc1ccccc1
Reactant: CC(=O)N1CCOCC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Product: C1COCCN1
Product: NC(=O)CC(=O)C#Cc1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Acetyl morpholine (546 ul, 4.72 mmole) was dissolved in 10 ml dry tetrahydrofuran in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C. and was treated slowly dropwise with lithium diisopropylamide (3.2 ml, 4.72 mmole). The mixture was stirred 30 minutes at 0° C. and was treated with methyl-2-benzyloxyphenyl propiolate (600 mg, 2.25 mmole) in 2 ml dry tetrahydrofuran. The reaction mixture was stirred for 1 hour at 0° C. and was diluted with 10 ml water. The volatiles were removed in vacuo and the residue was crystallized from diethyl ether/methanol (20:1). The tan solid was collected, was washed with diethyl ether, and was dried to afford 500 mg (61%) of morpholine-5-(2-Benzyloxyphenyl)-3-oxo-pent-4-ynamide as a tan solid. Melting Point: 224°-227° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]=1[OH:32])=[O:24]>>[C:23]([C:25]1[C:26]([OH:32])=[C:27]([NH:31][C:19]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][C:10]([CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][C:13]=3[CH:15]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:22]
Reactant: O=C(O)c1ccc2oc(COCc3ccccc3)cc2c1
Reactant: CC(=O)c1cccc(N)c1O
Product: CC(=O)c1cccc(NC(=O)c2ccc3oc(COCc4ccccc4)cc3c2)c1O
Yield: 98 %

Procedure:
Following the process described in example 1 (point K), starting from 2-(benzyloxymethyl)benzofuran-5-carboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared as a yellowish solid with melting point 92-94° C., which was purified by chromatography through a silica gel column (98% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55]([N:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:63]=1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccn4C(=O)OC(C)(C)C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 31.7 %

Procedure:
DIEA (0.009 mL, 0.053 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.010 g, 0.048 mmol) and HATU (0.02 g, 0.053 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (0.013 g, 0.048 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.007 g of product in 29% yield: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10][CH2:9]1)(=O)=O.O[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24](C#N)[CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:38][N:39](C)C=O>>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:28]2[CH:27]=[C:26]3[C:21](=[CH:20][CH:19]=2)[C:22]([C:38]#[N:39])=[CH:23][CH:24]=[CH:25]3)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)OCCN1CCSc2ccccc21
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc2cc(OCCN3CCSc4ccccc43)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
A mixture of 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethyl methanesulfonate (0.49 g, 1.82 mmol), 2-hydroxy-6-cyanonaphthalene (0.28, 1.65 mmol) and potassium carbonate (1.15 g, 8.28 mmol) in dry dimethyl formamide (15 mL) was stirred at 80° C. for 12 h. Water (50 mL) was added and extracted with ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with water (25 mL), brine (20 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether to afford the title compound (0.41 g, 72%) as a pale yellow solid. mp: 94-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)[C:6]([CH3:21])=[C:5]2[CH2:22]C(NCC(O)=O)=O.[CH2:30]([OH:32])C.[OH-:33].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:20])=[O:19])=[CH:16][CH:17]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:30]([OH:32])=[O:33]
Reactant: [OH-]
Reactant: CC1=C(CC(=O)NCC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Reaction time: 18 h

Procedure:
N-[5-fluoro-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenylacetyl]-glycine. Benzyle-N-[5-fluoro-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenylacetyl]-glycinate (0.03 mole) in a mixture of 25 ml. of anhydrous ethanol and 2.5 ml. of 1N sodium hydroxide is allowed to stand at room temperature for 18 hours. The solution is diluted with water and extracted with ether. The aqueous layer is acidified with dilute hydrochloric acid and the organic product is extracted with ethyl acetate, washed with water and dried over sodium sulfate. Evaporation of the solution gives N-[5-fluoro-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenylacetic acid, the corresponding indenyl acyl glycine is obtained, which can be converted to the corresponding sulfonyl derivative using the procedure of Example 1E.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:16]1[NH:21][CH2:20][CH2:19][N:18]2[CH2:22][CH2:23][CH2:24][C@@H:17]12.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>ClCCl.CO>[Cl:1][C:2]1[C:3]([C:4]([N:21]2[CH2:20][CH2:19][N:18]3[CH2:22][CH2:23][CH2:24][C@H:17]3[CH2:16]2)=[O:5])=[CH:7][C:8]([S:12]([NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[F:31])(=[O:14])=[O:13])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(Cl)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: C1C[C@H]2CNCCN2C1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl)N1CCN2CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To crude 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoyl chloride (4 mmol) in anhydrous dichloromethane (100 mL) was added (S)-octahydropyrrolo[1,2-α]pyrazine (0.505 g, 4 mmol) in dichloromethane (10 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.933 g, 8.8 mmol) was added. The mixture was stirred at room temperature overnight. Then dichloromethane was removed by concentration in vacuo, and 2-fluoroaniline (4.44 g, 40 mmol) in dichloromethane (30 mL) was added. The mixture was stirred at room temperature for 4 days. At that time, sodium carbonate (0.42 g, 4 mmol) and methanol (20 mL) were added, the mixture was stirred for 30 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then methanol/ethyl acetate=1:15) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.20-1.38 (m, 1H), 1.60-2.20 (m, 7H), 2.80-3.40 (m, 4H), 4.40-4.60 (m, 1H), 7.20 (m, 4H), 7.60 (m, 1H), 7.88 (m, 1H), 10.60 (br s, 1H); MS (ESI) m/z 456 (M+H)+.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[OH-:27].[Na+]>CN1CCCC1=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:3]([CH2:2][OH:27])=[C:4]([CH3:5])[N:6]=2)=[N:10]1
Reactant: [OH-]
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)oc1CO
Yield: 60 %

Procedure:
730 mg of 1,1-dichloro-3-[1(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (1.86 mmol) and 3.75 ml of NaOH, 1N (3.75 mmol) were stirred in 7.4 ml of N-methylpyrrolidone at 50° C. under argon overnight. After cooling, the mixture was poured onto ice-water and the product which had precipitated out was filtered off and dried. Finally, it was purified by column chromatography (SiO2, cyclohexane:ethyl acetate 2:1). 375 mg (60%) of 2-[1-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-methyl-oxazole were obtained as white crystals.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.C([O:10][C:11](=O)[CH2:12][N:13](C1C=CC=CC=1)[C:14](=[O:29])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)C>C(O)C>[O:29]=[C:14]1[NH:13][CH:12]([C:7]2[CH:6]=[CH:18][CH:17]=[CH:16][CH:21]=2)[C:11](=[O:10])[N:15]1[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CN(C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)NC(c3ccccc3)C2=O)CC1
Reaction time: 3 h
Yield: 81 %

Procedure:
Triethylamine (200 μL, 1.43 mmol) was added to a solution of tert-butyl 4-(3-(2-ethoxy-2-oxoethyl)-3-phenylureido)piperidine-1-carboxylate (90 mg, 0.22 mmol) in ethanol (1.8 mL). Reaction was held at 60° C. with stirring for 3 hours. Reaction mixture was concentrated in vacuo. Reside was treated with dichloromethane (20 mL) and then concentrated in vacuo. Title compound was obtained as white solid in 81% yield. MS m/e (M−C4H8+H)+=304.2.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:33]([CH:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][O:26][C:24](=[O:25])[CH2:23][CH2:22][S:21][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:34]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)CCSc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a suspension of methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) and potassium carbonate (13.9 g, 100 mmol) in DMF (120 mL) was added dropwise under ice-cooling 2-ethylhexyl 3-sulfanylpropanoate (12.1 g, 55.2 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:1) to give the title compound (20.0 g, quantitative).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([NH:12][C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)[C:4]([Br:11])=[C:5]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=12.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH:20]=[CH:19]1>C(O)C>[Br:11][C:4]1[C:3]([N:12]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18](=[O:24])[N:17]3[CH2:16][CH2:15][N:14]=[C:13]23)=[CH:2][CH:1]=[C:6]2[C:5]=1[N:10]=[CH:9][CH:8]=[N:7]2
Reactant: O=C1C=CC(=O)O1
Reactant: Brc1c(NC2=NCCN2)ccc2nccnc12
Solvent: CCO
Product: O=C(O)C1CC(=O)N2CCN=C2N1c1ccc2nccnc2c1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
Brimonidine (7.0 g) and maleic anhydride (3.53 g) were added to ethanol free chloroform (200 ml) and heated to 50° C. overnight. The solvent was evaporated and the residue slurried in MeCN (50 ml) at 30° C. for 2 h. The resultant solid was filtered washed with MeCN (25 ml) and dried in an oven at 40° C. to yield 10.5 g of 8-(5-bromoquinoxalin-6-yl)-5-oxo-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([I:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=2)[CH:17]=[C:8]([C:6]2[C:5]([I:23])=[CH:4][C:3]([F:24])=[C:2]([NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[CH:7]=2)[C:9]1=[O:22])[CH3:21]
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2I)cc2cnc(NC)cc21
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2I)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
A suspension of 3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.310 g, 0.707 mmol) in DCM (10 mL) was treated with phenyl isocyanate (0.100 g, 0.839 mmol) followed by pyridine (0.060 g, 0.759 mmol) and stirred at RT for 3 h. The mixture was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-iodophenyl)-3-phenylurea (120 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.77 (d, J=10.6 Hz, 1H), 7.64 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 7.05 (m, 2H), 6.24 (s, 1H), 4.14 (d, J=8.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 558.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1Cl
Temperature: 25 °C
Yield: 85137 %

Procedure:
A stirred solution of 5.8 grams (0.029 mmole) of 3,4,5-trichlorophenol (commercially available), 3.8 mL (0.032 mole) of benzyl bromide and 4.45 grams (0.032 mole) of potassium carbonate in 75 mL of DMF was warmed to 80° C. where it was maintained during a two-hour period. After this time the reaction mixture was allowed to cool to ambient temperature and then 150 mL of water was added. The mixture was extracted with three 50 mL portions of diethyl ether and the combined extracts were washed with one 50 mL portion of water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding 7.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(O)C>[NH:3]([CH2:1][CH3:2])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a stirring solution of ethylamine (24 mL, 300 mmol) and triethylamine (14 mL, 100 mmol) in ethanol (200 mL) at 0° C., was added via addition funnel a solution of t-butyl bromoacetate (19.5 mL, 100 mmol) in ethanol (50 mL). The cold bath was left unattended and the mixture was allowed to slowly warm to room temperature. After 24 hours, the solvents were removed in vacuo. The residue was dissolved in ethyl acetate, and extracted twice with 1N citric acid. The combined aqueous layers were basified to pH 10 with solid Na2CO3, and then extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4), filtered, and concentrated in vacuo to give 9.8 g (62%) of a yellow oil.