Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([O:7][C:8](=[O:40])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:21]([CH3:22])=[CH:20][N:19]([CH:23]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=2)[O:24][CH2:25][CH3:26])[N:18]=1)C.[Na].CCOC(C)=O.CC(C)=O.O.CC(O)=O>C(O)C.O>[C:1]([OH:4])(=[O:3])[CH3:2].[C:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][C:27]([CH:23]([O:24][CH2:25][CH3:26])[N:19]2[CH:20]=[C:21]([CH3:22])[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][C:8]([OH:40])=[O:7])=[N:18]2)=[O:39])=[CH:35][CH:34]=1)(=[NH:37])[NH2:38]
Reactant: CCOC(=O)COc1ccccc1-c1nn(C(OCC)C(=O)NCc2ccc(C(=N)N)cc2)cc1C
Agent: [Na]
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)n1cc(C)c(-c2ccccc2OCC(=O)O)n1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred mixture of (RS)-(2-{1-[(4-carbamimidoyl-benzylcarbamoyl)-ethoxy-methyl]-4-methyl-1H-pyrazol-3-yl}-phenoxy)-acetic acid ethyl ester acetate (82 mg) at r.t. in ethanol/H2O 1:1 (2 ml) was added sodium hydroxyde (20 mg). Stirring was then continued for 2 h. The mixture was concentrated to leave an off-white paste. The crude product was isolated by chromatography (silica gel, EtOAc/acetone/H2O/HOAc 6:2:1:1) to give (RS)-(2-{1-[(4-carbamimidoyl-benzylcarbamoyl)-ethoxy-methyl]-4-methyl-1H-pyrazol-3-yl}-phenoxy)-acetic acid acetate (58 mg) as an off-white solid. MS 466.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][CH:12]([C:16]([F:19])([F:18])[F:17])[C:13](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:13]([CH:12]([F:11])[C:16]([F:19])([F:18])[F:17])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (2.03 g; 11.5 mmoles) and 2,3,3,3-tetrafluoro-propionic acid (1.99 g; 13.6 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (60 mL) and with ethyl acetate (60 mL), then sodium bicarbonate (4.02 g; 47.9 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid. A sample of the crude brown solid was purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light orange solid.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[OH-].[Na+].[O:8]=[C:9]1[C:18](=[O:19])[NH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:20](Cl)(=[O:22])=[O:21])[CH:15]=2)[NH:10]1>O>[Br:2][CH2:3][CH2:4][NH:5][S:20]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:8])[C:18](=[O:19])[NH:17]2)(=[O:21])=[O:22]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2ccc(S(=O)(=O)NCCBr)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.9 %

Procedure:
20.49 g (0.1 mole) of 2-bromoethylamine hydrobromide and 4.00 g (0.1 mole) of sodium hydroxide are dissolved in 60 ml of water, and 7.82 g (0.03 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added to the solution, and the mixture is stirred at room temperature for 6 hours. Then it is allowed to stand for 16 hours. The separated crystals are filtered, washed successively with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from the solution with water. Thus 3.44 g (33%) of N-(2-bromoethyl)-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 261-266° C.
Reaction SMILES: [N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[N+:2]=[N-:3].C1C=C(Cl)C=C(C(OO)=[O:45])C=1>C(Cl)Cl>[N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:45])[C@H:5]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[N+:2]=[N-:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CO[C@H]2[C@H](N=[N+]=[N-])[C@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@H](N=[N+]=[N-])[C@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2S(=O)c2ccccc2)cc1
Temperature: -20 °C

Procedure:
To a solution of phenyl 3-azido-4-O-benzoyl-3,6-di-deoxy-2-O-(4-methoxybenzyl)-1-thio-β-L-galactopyranoside (β-16, prepared above), (350 mg, 0.7 mmol) in 10 mL of CH2Cl2 at -78° C. is added a solution of mCPBA (170 mg, 1.1 mmol) in 2 mL of CH2Cl2. The reaction mixture is allowed to warm to -20° C. and then quenched with TEA (500 μL, 3.59 mmol). The reaction mixture is diluted with 10 mL of CH2Cl2, washed with saturated NaHS3 (10 mL), saturated NaHCO3 (10 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (EtOAc/petroleum ether) to give the title compound as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[OH-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Yield: 51.9 %

Procedure:
To a solution of 3-nitroaniline (0.5 g, 3.6 mmol) in 10 ml acetic acid added bromine (0.2 ml, 4.0 mmol) and stirred at 0° C. for 1 hour. The solution was filtered after recovering to room temperature to obtain 2-bromo-5-nitrobenzenamine (0.32 g, 40%) as a powder. A solution of 2-bromo-5-nitrobenzenamine (0.4 g, 1.8 mmol), sodium hydroxide (0.14 g, 3.6 mmol) and benzoyl chloride (0.24 ml, 2.0 mmol) in 20 ml THF was stirred for 2 hours in icy water bath. The reaction was quenched and washed with water (3×20 ml). The mixture was dried over anhydrous sodium sulfate. The crude N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 50%) was obtained after evaporation of the solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (m, 2H), 7.68 (m, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.7 Hz, 1H), 8.00 (m, 2H), 8.62 (s, 1H), 9.55 (d, J=2.7 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[OH-].[Na+]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)c(C(F)(F)F)c1
Yield: 81 %

Procedure:
1.91 g (10 mmol) of 3-nitrobenzotrifluoride, 1.88 g (20 mmol) of 2-aminopyridine and 1.2 g (30 mmol) of sodium hydroxide in the form of microbeads are heated at 50° C. for 6 h in 30 ml of abs. DMSO while passing through dry air. After cooling, the mixture is diluted with ethyl acetate and extracted several times by shaking with water. After drying and stripping off the organic solvent, 3.8 g of crude product are obtained which is purified by chromatography on silica gel using petroleum ether and ethyl acetate (volume ratio 1:1). 2.3 g (8.1 mmol, 81%) of 2-(4-nitro-2-trifluoromethylphenylamino)-pyridine of m.p. 83°-84° C. are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([SH:11])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+].C(O)C>O>[CH2:13]([S:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(O)c1cc(Cl)ccc1S
Reactant: O=C(CCl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CSc1ccc(Cl)cc1C(=O)O)c1ccccc1

Procedure:
A solution of 18.9 g. (0.1 mole) of 5-chlorothiosalicylic acid, 15.4 g. (0.1 mole) of α-chloroacetophenone and 8 g. (0.2 mole) of sodium hydroxide in 200 ml. of ethanol containing 45 ml. of water is heated to reflux for 2 hours. After removing one-fourth the alcohol under reduced pressure, the mixture is acidified with hydrochloric acid and the resulting precipitated product filtered, 5.0 g., m.p. 154°-156° C. The analytical sample has a melting point of 156°-157.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COc1ccc(CN(C)C2CCOCC2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccc(O)cc1)C1CCOCC1
Reaction time: 2 h
Yield: 10 %

Procedure:
Into a solution of N-methyl-N-(tetrahydropyran-4-yl)-4-methoxybenzylamine (2.19 g) in dichloromethane (20 ml) was added at −78° C. a solution of boron tribromide in dichloromethane (11 ml). After gradually raising the temperature from −78° C. to room temperature, the resulting mixture was stirred for 2 hours, an additional solution of boron tribromide in dichloromethane (5 ml) was again added thereto, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was mixed with an aqueous solution of sodium bicarbonate under ice cooling and was extracted with dichloromethane, and the extract was concentrated under reduced pressure. Thereto were added 1 N hydrochloric acid and diethyl ether to extract the aqueous layer. The extract was adjusted to pH 8 by adding an aqueous solution of potassium carbonate and was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was then concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/methanol) to obtain N-methyl-N-(tetrahydropyran-4-yl)-4-hydroxybenzylamine (206 mg) as a light yellow, oily substance.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([C:12]2[CH:17]=[N:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:27]([F:41])[CH:26]=3)[N:13]=2)[CH2:7]1)(=O)=O.[CH3:42][S-:43].[Na+]>CO>[CH2:33]([NH:32][C:31](=[O:40])[C:28]1[CH:29]=[CH:30][C:25]([C:14]2[C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[N:16][CH:17]=[C:12]([C@@H:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([S:43][CH3:42])[CH2:7]3)[N:13]=2)=[CH:26][C:27]=1[F:41])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C[S-]
Reactant: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](OS(C)(=O)=O)C2)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Agent: [Na+]
Solvent: CO
Product: CS[C@@H]1CCC[C@@H](c2cnc(NC(=O)C(C)(C)C)c(-c3ccc(C(=O)NCc4ccccc4)c(F)c3)n2)C1
Temperature: 80 °C
Yield: 108.7 %

Procedure:
A mixture of (+/−)-(1S,3R)-3-(6-(4-(benzylcarbamoyl)-3-fluorophenyl)-5-pivalamidopyrazin-2-yl)cyclohexyl methanesulfonate (25 mg, 0.043 mmol) and sodium methanethiolate (24.09 mg, 0.344 mmol) in MeOH (430 μL) was heated at 80° C. for 2 h. Solvent was removed and the residue was purified with flash chromatography eluting with EtOAc (containing 10% of MeOH)/heptane to provide 25 mg of crude (+/−)-N-benzyl-2-fluoro-4-(6-((1R,3R)-3-(methylthio)cyclohexyl)-3-pivalamidopyrazin-2-yl)benzamide which was taken to the next step without further purification. LCMS (m/z): 535.3 (MH+), 1.09 min.
Reaction SMILES: [Br:1]Cl.[C:3]([Cl:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.BrBr.ClCl>[Fe]>[Br:1][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([Cl:11])=[O:10]
Reactant: ClBr
Reactant: O=C(Cl)c1ccccc1
Agent: [Fe]
Agent: BrBr
Agent: ClCl
Product: O=C(Cl)c1cccc(Br)c1

Procedure:
When using bromine chloride as the brominating agent, the bromine chloride can be preformed or formed in situ, and the latter is preferred. In accordance with this preferred procedure, benzoyl chloride, bromine and iron powder are charged to a reactor and the reactor contents are cooled to a temperature in the range of about 0 to about 60° C., preferably about 10° C., and chlorine is slowly fed into the reactor whereby bromine chloride is formed in situ. The bromine chloride reacts with the benzoyl chloride to form m-bromobenzoyl chloride (MBBC). Usually the reaction is performed at a temperature the range of about -10 to about 60° C., preferably at about 10° C. for a period in the range of about 1 to about 24 hours, and typically for about one hour after completion of the chlorine feed. The reaction mixture is then stripped with an inert gas, preferably nitrogen, for 1 to 24 hours at a temperature in the range of about 25 to about 120° C., preferably for two to three hours at about 60 to 90° C., followed by further stripping while cooling to ambient room temperature (ca. 25° C.). During the reaction and subsequent stripping operations, the exit gases are passed through suitable scrubbers to remove purged HCl, and unreacted bromine. The major residual byproducts of the bromination are m-chlorobenzoyl chloride, chlorobromobenzoyl chlorides, and dibromobenzoyl chlorides. The crude MBBC can be purified by distillation at reduced pressure, for example at 160° C. and 60 mm Hg pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:32]([C:27]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=3)(=[O:34])=[O:33])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc12
Yield: 43.4 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide can be obtained as described in Example 1 from 1 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 50 ml of tetrahydrofuran, 1.15 ml of triethylamine and 1.1 g of 3,4-dichlorobenzenesulfonyl chloride. 0.8 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide is thus obtained in the form of a white solid melting at 171° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][CH:16]1[CH2:19][CH2:18][CH2:17]1.[OH-].[Na+].Cl>O1CCCC1>[CH:16]1([CH2:15][O:14][C:5]2[CH:6]=[CH:7][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[C:3]([OH:20])=[O:2])[CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OCC1CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(OCC2CCC2)c(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To 6.51 mmol 2-cyclobutylmethoxy-5-methanesulfonyl-benzoic acid methyl ester in 20 ml tetrahydrofuran was added 40 mmol 2 N aq NaOH solution and the reaction mixture was stirred at 60° C. for 2 hours. After such time the reaction mixture was acidified by addition of concentrated HCl and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether to give the title compound as a white solid (40% over 2 steps). MS (m/e): 283.3 ([M−H]−, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]2[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[N:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Li+].I[CH3:23]>COCCOC.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][N:10]([C:11]3[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=3[F:17])[C:5]2=[N:4][C:3]=1[O:19][CH3:23]
Reactant: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)nc1Br
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COc1nc2c(cnn2-c2c(F)cccc2F)nc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
A mixture of 5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (981 mg, 3.0 mmol) in 10 mL of DME and 1 mL of DMF at RT was treated with lithium hydride (119 mg, 15 mmol) in small portions. Iodomethane (0.62 mL, 9.9 mmol) was added 30 min later. The mixture was stirred at RT for 18 h, and poured into an ice cold sat. NH4Cl solution, then extracted twice with EtOAc. The combined EtOAc layes were washed with brine, dried and concentrated. Purification of the crude material on a silical gel column (25-85% EtOAc in Hexanes) provided: (1) 5-bromo-1-(2,6-difluorophenyl)-6-methoxy-1H-pyrazolo[3,4-b]pyrazine (65 mg, 6.4% yield) as an off white crystalline solid. MS (ES+): 341.0/343.0 (M+H)+; and (2) 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (616 mg, 60% yield) as an off white amorphous solid. MS (ES+): 341.0/343.0 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:25][CH:26]=1)=[O:20].O>O1CCCC1>[C:1]1([CH2:7][C:8]([O:10][CH2:18][C:19](=[O:20])[C:21]2[CH:26]=[N:25][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:23][CH:22]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(CBr)c1cnc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccccc1)OCC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 40 °C
Yield: 57.7 %

Procedure:
To a solution consisting of phenylacetic acid (27 mg, 0.20 mmol) and cesium carbonate (117 mg, 0.360 mmol) in tetrahydrofuran (1.5 mL) at room temperature was added 2-bromo-1-(2-phenylpyrimidin-5-yl)ethanone (Step B, 50 mg, 0.18 mmol). The reaction mixture was heated at 40° C. for one hour and cooled to room temperature. To the mixture was added water (10 mL) with vigorous stirring and the precipitate was filtered, washed with water, and dried on the suction filter to provide 2-oxo-2-(2-phenylpyrimidin-5-yl)ethyl 2-phenylacetate as a tan solid (34.5 mg, 57% yield) as an isolated intermediate. The tan solid was dissolved in toluene (4 mL) and freshly prepared ammonium acetate under toluene (300 mg wet with toluene) was added and the mixture was stirred vigorously and heated in a capped vial at 112° C. overnight. The brown reaction mixture was poured into aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness. The brown solid was dissolved in dichloromethane and chromatographed on a 4 g silica column eluted with 1:4:5 to 1:6:3 dichloromethane-ethyl acetate-hexane to afford the title compound as a tan solid; Rf 0.08 with 6:4 v/v hexanes-ethyl acetate and Rf 0.61 with 3:7 v/v hexanes-ethyl acetate; melting point 235° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.21 (s, 2H), 8.3-8.5 (m, 2H), 7.82 (d, 1H), 7.5-7.6 (m, 3H), 7.2-7.4 (m, 5H), 4.08 (s, 2H); MS (ESI+) m/z 313 (M+1); H-PGDS FPBA IC50: 0.625 μM; H-PGDS inhibitor EIA IC50: 0.059 μM.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([N+:16]([O-])=O)[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[N:4]1)[CH3:2]>CO.O.[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:11]2[C:6]=1[CH:5]=[N:4][N:3]2[CH2:1][CH3:2]
Reactant: CCn1ncc2c([N+](=O)[O-])cc(C(=O)OC)cc21
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCn1ncc2c(N)cc(C(=O)OC)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of methyl 1-ethyl-4-nitro-1H-indazole-6-carboxylate (D198) (2.2 g, 8.8 mmol, 1 equiv) in MeOH (100 ml) and H2O (10 ml) was added 10% palladium on charcoal (50% wet, 700 mg, 16% w/w) and the resulting mixture was stirred at 60° C. for 30 min then cooled to room temperature. The catalyst was removed by filtration through a pad of celite and most of the solvent removed in vacuo. The residue was partitioned between AcOEt and a saturated aqueous NaHCO3 solution and the two layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane to give methyl 4-amino-1-ethyl-1H-indazole-6-carboxylate (D199) (1.55 g, 80%) which was used in the next step without further purification. [M+H]+=220.1, RT=3.31 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:4].[CH3:33][N:34]([C:36]1[S:37][CH:38]=[CH:39][N:40]=1)[NH2:35].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Li+]>ClCCCl.[Cl-].[Na+].O.O.CO>[CH3:31][C:29]([CH3:30])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:18]([CH:20]2[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]2)=[O:19])[CH:11]2[CH2:16][CH2:15][CH:14]([NH:35][N:34]([CH3:33])[C:36]3[S:37][CH:38]=[CH:39][N:40]=3)[CH2:13][CH2:12]2)[CH:8]=1
Reactant: CN(N)c1nccs1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(NN(C)c3nccs3)CC2)CC1
Reaction time: 5 h
Yield: 14.7 %

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (200 mg, 0.44 mmol) and N-Methyl-N-thiazol-2-yl-hydrazine (112 mg, 0.87 mmol) in DCE (4 mL) was treated with AcOH (200 μL, 3.0 mmol) followed by NaBH(OAc)3 (120 mg, 0.57 mmol) in two portions. After 5 h, NaHCO3 (saturated aqueous solution, 3 mL) was added to the mixture, followed by brine (20 mL), and the crude product was extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated and the crude material was dissolved in a 3:2:1 mixture of THF:MeOH:water (20 mL), treated with lithium hydroxide (2.2 mmol, 92 mg) and heated to 60 deg C. for 1 hours. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-100% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 36 mg of the title compound as its trans isomer (TFA salt): MS (m/z): 557.2 [M−H]+; HPLC retention time: 3.43 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid) and 8 mg of the title compound as its cis isomer (TFA salt): MS (m/z): 557.2 [M−H]+; HPLC retention time: 3.41 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).