Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:9][O:10]C)[C:3]=1[O:15][CH:16]([F:18])[F:17]>C1COCC1.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:12]2[CH2:13][CH2:14]2)[CH:9]=[O:10])[C:3]=1[O:15][CH:16]([F:18])[F:17]
Reactant: COC=C(c1nccc(Cl)c1OC(F)F)C1CC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=CC(c1nccc(Cl)c1OC(F)F)C1CC1
Yield: 79.2 %

Procedure:
6.00 g of 2-(4-chloro-3-difluoromethoxy-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI) was dissolved in 60 ml of THF, to which 40 ml of dilute sulfuric acid was added, and the resulting mixture was concentrated at 50° C. under reduced pressure. The resulting mixture was poured into water and neutralized with saturated sodium bicarbonate solution, and thereafter, extracted with chloroform. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 4.51 g of 2-(4-chloro-3-difluoromethoxy-2-pyridyl)-2-cyclopropylethanal (XII).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: c1ccc(CN2CCC(n3cnc4ccccc43)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc2c(c1)ncn2C1CCNCC1
Temperature: 25 °C
Yield: 118.2 %

Procedure:
To a solution of 196 mg of 1-(1-benzyl-piperidin-4-yl)-1-H-benzoimidazole (from Step B) in 10 mL of CH3OH was added 200 mg 10% palladium on carbon and 200 mg ammonium formate. After the reaction was refluxed for 4 hours, the mixture was cooled down to room temperature, filtered through Celite and washed with CH3OH. The filtrate was concentrated under reduced pressure to give 160 mg of the title compound as oil. 1H NMR (400 MHz, CD3OD): δ2.13(m, 4H), 2.92(m, 2H), 3.27(m, 2H), 4.56(m, 1H), 7.28(m, 2H), 7.66(t, J=5.9 Hz, 2H), 8.25(s, 1H). ESI-MS 201 (M+H); HPLC A: 0.61 min.
Reaction SMILES: [F:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.[OH-].[K+]>CN(C)C=O>[F:1][C:2]([F:6])([O:13][C:12]1[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][CH:11]=1)[CH:3]([F:5])[F:4]
Reactant: Cc1ccc(O)cc1
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(OC(F)(F)C(F)F)cc1
Temperature: 68 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
For one hour, tetrafluoroethylene and nitrogen are bubbled into a magnetically stirred mixture of 10.8 g (0.100 mol) of p-cresol, 1.67 g (1.43 g real, 0.0255 mol) of potassium hydroxide pellets, and 70 ml of dried dimethylformamide (DMF) maintained at 68° C. After dilution with 250 ml of water, the reaction mixture is extracted with 100 ml of ether. The ether solution is washed with 200 ml of 5% sodium hydroxide and twice with 400 ml of water. The ether solution is dried, filtered, and then rotary evaporated to give 18.14 g (87%) of p-(1,1,2,2-tetrafluoroethoxy)toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](C(OC(C)(C)C)=O)[CH:8]=[C:7]2[C:18]1[N:27]=[CH:26][C:25]2[NH:24][CH2:23][CH:22]3[CH2:28][O:29][CH2:30][CH2:31][N:21]3[C:20]=2[N:19]=1.C(Cl)Cl.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:18]1[N:27]=[CH:26][C:25]2[NH:24][CH2:23][CH:22]3[CH2:28][O:29][CH2:30][CH2:31][N:21]3[C:20]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ncc3c(n2)N2CCOCC2CN3)c2cccc(Cl)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)c[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A mixture of tert-butyl 7-chloro-3-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-1H-indole-1-carboxylate and CH2Cl2/TFA (1:1) was heated to 50° C. and stirred for 2 hours. The reaction mixture was subsequently concentrated in vacuo and the crude product purified by LC/MS using a gradient of 30-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a tan solid (20 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ 2.98-3.01 (m, 2H), 3.56-3.58 (m, 3H), 3.72-4.25 (m, 3H), 4.65-4.92 (m, 1H), 6.34-6.58 (br s, 1H), 7.12-7.59 (m, 3H), 8.12-8.52 (m, 2H), 12.27-12.56 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H16ClN5O, 342.10. found 342.3.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[N:24]1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=5)=[CH:31][C:26]=4[N:25]=[N:24]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCn1nnc2cc(C3=NNC(=O)CC3)ccc21
Product: O=C1CCC(c2ccc3c(c2)nnn3CCNCC(O)COc2ccc(CCOCC3CCC3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6- [1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[CH:13][CH:14]=[N:15]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([S:8][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[CH:13][CH:14]=[N:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Br)c2nccnc2c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cc(SCc2ccccc2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl mercaptan (0.51 g, 4.1 mmol) was added dropwise to a mixture of 5-bromo-7-chloroquinoxaline (1 g, 4.1 mmol), cesium carbonate (1.6 g, 4.92 mmol) at 0° C. in DMF (25 ml) under nitrogen. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried with sodium sulfate and concentrated. Purification by column chromatography gave 5-(benzylthio)-7-chloroquinoxaline (rf=0.39 in 9:1 hexanes/ethyl acetate) as a yellow solid. The undesired regioisomer elutes afterwards (rf=0.27 in 9:1 hexanes/ethyl acetate).
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9](Cl)=[O:10])[CH:5]=1>C(Cl)Cl>[Cl:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([NH2:1])=[O:10])[CH:5]=1
Reactant: N
Reactant: O=C(Cl)c1cc(CCl)on1
Solvent: ClCCl
Product: NC(=O)c1cc(CCl)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Ammonia was passed for 1 hour at 10-15° C. into a solution of 10 g (55.56 mmol) of 5-chloromethylisoxazole-3-carboxylic acid chloride in 100 ml of methylene chloride and stirring was subsequently continued at room temperature for 1 hour. After the solution had cooled to 0° C., the precipitate was filtered off with suction and washed with a little cold methylene chloride, and the residue was extracted twice by stirring with water to remove the ammonium salts. Drying in vacuo resulted in 6.58 g of pure product as a pale powder (74% of theory)
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.ClC1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:32]([C:29]1[CH:28]=[N:27][C:6]([NH:7][C@H:8]2[CH2:9][C@H:10]([N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[C:14]([CH3:21])([CH3:22])[C:13]3=[O:23])[CH2:11]2)=[N:31][CH:30]=1)[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cnc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
1-(Trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 100 mg, 0.329 mmol), 2-chloro-5-ethylpyrimidine (0.047 mL, 0.329 mmol), and potassium carbonate (0.079 mL, 1.315 mmol) were mixed in DMSO (0.7 mL) in a microwave vial. The reaction mixture was stirred at 80° C. for 16 hours. The temperature was increased to 100° C. and the reaction stirred for another 9 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The resulting crude product was purified via silica gel flash column chromatography eluting with 0 to 100% ethyl acetate in hexanes to yield 1-(trans-3-((5-ethylpyrimidin-2-yl)amino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one as an off-white solid. M+1: 338.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.63 Hz, 3 H) 1.31 (s, 6 H) 2.26-2.37 (m, 2 H) 2.43 (q, J=7.63 Hz, 2 H) 3.15-3.26 (m, 2 H) 4.47-4.62 (m, 1 H) 5.16 (quin, J=8.20 Hz, 1 H) 7.07 (dd, J=7.24, 5.28 Hz, 1 H) 7.48 (d, J=6.46 Hz, 1 H) 7.75 (dd, J=7.24, 1.76 Hz, 1 H) 8.21 (dd, J=5.28, 1.56 Hz, 2 H)
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[H][H]>[Pd].C(O)CCC>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
0.07 Gram of 5% palladium on carbon catalyst was added to a mixture of 7.7 grams of 5-nitrotetrahydroanthraquinone and 240 grams of butanol, which was then heated up to 50° C. Hydrogen was then fed into the solution under normal pressure to absorb hydrogen in an amount of 2 mols per mol of the starting 5-nitro compound. After separation of the catalyst by filtration, 4.0 grams of crystal sodium carbonate was added to the reaction solution while agitating at a temperature of 100° C. for 1 hour. Thereafter, hydrochloric acid was added to the reaction solution for neutralization, then butanol was distilled off from the solution until crystals began to precipitate. After allowing to cool, the reaction solution was filtered and the crystals were washed with water and dried to obtain 6.0 grams of 1-aminoanthraquinone having a purity of 97.2%.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:45]=[C:44]([CH3:46])[O:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1cc(C)on1
Product: Cc1cc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(F)c2F)no1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,5-dimethyl-1,2-oxazole-3-carboxamide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC(=O)[NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH:52]([NH2:56])[CH2:51]1)(C)(C)C.C(OC(=O)NC1CCCN(C(C2C=CC(C3C=C(Cl)C(CC4CCN(C5CCCCC5)C4=O)=C(Cl)C=3)=CC=2)=O)C1)(C)(C)C.Cl.O1CCOCC1>ClCCl.O1CCOCC1>[NH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH:52]([NH:56][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][CH:9]4[CH2:13][CH2:12][N:11]([CH:14]5[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]5)[C:10]4=[O:20])=[C:6]([Cl:21])[CH:5]=3)=[CH:27][CH:26]=2)=[O:30])[CH2:51]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(N)C1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: CC(C)(C)OC(=O)NC1CCCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCCC(NC(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)C1
Temperature: 25 °C

Procedure:
Dissolve racemic 3′, 5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (1.00 eq.) in dichloromethane (5-10 mL) and add 1,1′-carbonyl-diimidazole (1.50 eq.). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add (3-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.05-2.0 eq.) and continue to stir, checking progress via LC/MS. Once starting material has been fully consumed, dilute reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) and brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient of 100% dichloromethane to 10% ammonia methanol/90% dichloromethane to recover {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester. Dissolve the {1-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir 30 min. Concentrate under vacuum, dilute in dichloromethane (100 mL) and add saturated aqueous sodium bicarbonate (50 mL). Dry the organic phase with magnesium sulfate and concentrate to a foam: MS (m/z): 528 (M+).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C.CN1CCCC1=O>O>[N+:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH:18][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CCCCC(=O)Cl
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
121 parts of valeryl chloride are added to a mixture of 181 parts of p-nitrobenzoic acid hydrazide, 101 parts of triethylamine and 1,000 parts of N-methylpyrrolidone, while cooling with ice. The solution is then stirred for a further 4 hours at room temperature, after which it is poured into 5,000 parts of water, and the resulting precipitate is filtered off under suction, washed with water and dried. 250 parts (95% of theory) of N-(p-nitrobenzoyl)-N'-valerylhydrazine of melting point 185°-187° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1
Reactant: Brc1ccnnc1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccnnc1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a degassed mixture containing 4-bromopyridazine (0.10 g, 0.63 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.18 g, 0.69 mmol), sodium carbonate (0.27 g, 2.52 mmol), dioxane (5.2 mL) and water (1.01 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) in one portion under a nitrogen atmosphere. The mixture was heated with fast stirring at 95° C. for 4 h, cooled to room temperature and filtered. The filtered solution was acidified to below pH 4 with 1N HCl (5.0 mL). The resultant precipitate was recovered by filtration, washed with water (3×3.0 mL) and air dried. The resultant tan solid was suspended in n-pentane (4 mL), stirred for 20 min, recovered by filtration and air dried to afford 4-methyl-3-(pyridazin-4-yl)benzoic acid as a tan solid which was used without further purification. LCMS: retention time: 1.325 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire, 5 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 215 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[Br:11])=[N+:2]=[N-:3].[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[N:1]1[CH:17]=[C:16]([Si:13]([CH3:15])([CH3:14])[CH3:12])[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1cc(F)ccc1Br
Reactant: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cn(-c2cc(F)ccc2Br)nn1
Temperature: 110 °C
Yield: 95.2 %

Procedure:
A mixture of 2-azido-1-bromo-4-fluorobenzene (1.047 g, 4.85 mmol) and trimethylsilylacetylene (2.01 mL, 14.54 mmol) in toluene (5 mL) was heated in a pressure vessel at 110° C. for 21.5 h. The reaction mixture was concentrated in vacuo and the residue was purified with a Biotage system on silica gel with hexanes:ethyl acetate (9:1) gradient as the eluent to afford the title compound as a colorless oil (1.451 g, 95% yield): 1H NMR (400 MHz, CDCl3) o ppm: 7.97 (1H, s), 7.74 (1H, dd, J=9.0, 5.4 Hz), 7.37 (1H, dd, J=8.5, 2.9 Hz), 7.16 (1 H, ddd, J=8.8, 7.6, 3.0 Hz), 0.40 (9 H, s), LCMS (+ESI, M+H+) m/z 314/316.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]3[NH2:36])[CH2:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C@@H:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]3[NH:36][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=3)=[O:11])[CH2:24]2)=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 5.7 %

Procedure:
1-((1R,2R)-2-((S)-1-(4-Nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea was synthesized as described in General Procedure F using 4-trifluoromethyl-phenyl isocyanate (13 mg, 0.069 mmol) and (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (30 mg, 0.069 mmol) to give 1-((1R,2R)-2-((S)-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea as a yellow solid (2.0 mg, 54% yield). Anal. Calcd. for C25H30F3N5O3 m/z 505.5, found: 506.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 9.61-8.86 (m, 1H), 8.76 (br. s., 1H), 7.72 (d, J=8.80 Hz, 2H), 7.42-7.33 (m, 2H), 7.30 (d, J=8.25 Hz, 2H), 7.06 (br. s., 1H), 6.66 (d, J=8.80 Hz, 2H), 3.75-3.56 (m, 2H), 3.48 (d, J=12.65 Hz, 1H), 3.44-3.29 (m, 2H), 3.25 (d, J=7.70 Hz, 1H), 3.11 (br. s., 1H), 2.24-2.00 (m, 4H), 1.86 (d, J=13.20 Hz, 3H), 1.84-1.75 (m, 1H), 1.71 (d, J=11.00 Hz, 1H), 1.49 (br. s., 1H) 1.37-1.17 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 154.35, 144.05, 125.87, 125.55, 123.02, 120.76, 117.83, 114.19, 66.81, 63.17, 52.86, 52.53, 48.20, 31.08, 28.87, 26.95, 23.72, 22.69, 21.03.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([OH:10])=[N:9][C:4]2=[CH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O>ClCCl.CN(C=O)C>[Br:11][C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][C:8]([OH:10])=[N:9][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccn2nccc2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Oc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.9 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidin-5-ol (Example 1, Step 1, 28.3 g, 210 mmol) and N-bromosuccinimide (37.3 g, 210 mmol) in dichloromethane (200 mL) and DMF (300 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was concentrated and the product was precipitated using Et2O. The solids were collected by filtration and dried to afford 3-bromopyrazolo[1,5-a]pyrimidin-5-ol (40.4 g, 90%). LCMS (APCI−) m/z 211, 213 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][C@H:8]([C:19](=[O:40])[NH:20][C@H:21]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH2:27][O:26][CH2:25][CH2:24][NH:23][C:22]1=[O:39])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].I[CH2:43][CH2:44][CH2:45][OH:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:41])[CH2:7][C@H:8]([C:19](=[O:40])[NH:20][C@H:21]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH2:27][O:26][CH2:25][CH2:24][NH:23][C:22]1=[O:39])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:43][CH2:44][CH2:45][OH:46])=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCI
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccc(O)cc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccc(OCCCO)cc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.9 %

Procedure:
To (3R,9S)-6-[4-hydroxyphenyl]-3-[8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid t-butyl ester (1.0 g, 1.72 mmol) in DMF (20 mL) at 0° C. was added 3-iodopropanol(363mg, 1.95 mmol) and cesium carbonate (636 mg, 1.95 mmol). The mixture was then stirred at room temperature for 2.5 hours. DMF was removed under reduced pressure. The remaining residue was taken up in EtOAc (70 mL) and brine (40 mL). The EtOAc layer was washed with brine and dried (MgSO,). Removal of solvents to give pure (3R,9S)-6-[4-(3-hydroxy-propoxy)-phenyl]-3-[8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid t-butyl ester (1.1 g, 100%), MS: 622.4 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:23]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:7][CH:6]=1)[C:3]([OH:24])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCCOc2ccccc2)cc1
Yield: 86 %

Procedure:
A mixture of alpha-oxo-4-[[(4-phenoxy)butyl]oxy]benzeneacetic acid methyl ester (0.85 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided material which was crystallized from diethyl ether-hexane to give 0.7 g of colorless alpha-oxo-4-[[(4-phenoxy)butyl]oxy]benzeneacetic acid, mp 103°-105° C.