Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(OC)[C:21](=[O:30])[C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH2:29].C([Li])CCC.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:21]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[NH2:29])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)c2cc(Cl)ccc2N)C1
Temperature: -78 °C
Yield: 23.3 %

Procedure:
In tetrahydrofuran (15 ml) were dissolved N-tert-butoxycarbonyl-5-bromo-1,2,3,4-tetrahydroisoquinoline (0.9 g) and N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (0.68 g). The solution was cooled to −78° C., to which was added dropwise, while stirring, n-butyl lithium (1.6 mol, hexane solution) (9 ml) over 30 minutes. To the reaction mixture was added water (50 ml) to decompose, followed by extraction with ethyl acetate (80 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(N-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)carbonyl-4-chloro-aniline (0.26 g) as a yellow crystalline product. m.p.: 159-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[C:6]([CH:7]=O)=[CH:5][N:4]=1.[NH3:17]>CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:9]([CH:10]=1)=[CH:11][CH:12]=[N:17][CH:7]=2
Reactant: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Reactant: N
Solvent: CO
Product: COc1cc2ccncc2cn1

Procedure:
6-Methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde (0.25 g, 1.1 mmol) and 7M ammonia in MeOH (5 mL) were stirred in a sealed vial at 80° C. overnight. The solution was concentrated, taken up in saturated sodium carbonate and extracted with ether. The organic phase was dried, filtered and concentrated to give 0.20 g of the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].C1C[O:13][CH2:12]C1.CN(C)C=O>>[CH:12]([C:5]1[O:4][C:3]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[CH:6]=1)=[O:13]
Reactant: Cc1ccoc1C(=O)O
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C=O)oc1C(=O)O
Temperature: -70 °C

Procedure:
3-Methyl furoic acid (10 g, 79 mmol) and THF (400 mL) n-butyl lithium (67 mL, 0.167 mol) were stirred at a rate sufficient to maintain −70° C. (approx. 1 drop per sec). min then dimethylformamide (30 g, 0.395 mol) was added all at once. The reaction temperature was maintained for an additional 3 hr. After this time the reaction was quenched with the addition of saturated ammonium chloride. The aqueous phase was acidified with 6 N HCl, after extraction and recrystallized from water Intermediate 6 was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH:19]=[CH2:20])[C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OC)(C)(C)C.[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=3[S:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCc1c(O)ccc2c(CCc3ccccc3)csc12
Agent: [Pd]
Solvent: COC(C)(C)C
Product: CCCc1c(O)ccc2c(CCc3ccccc3)csc12
Reaction time: 1 h

Procedure:
The product from Step G (3.062 grams) was dissolved in methyl tert-butyl ether (60 mL) and placed in a hydrogenation bottle. 5% Pd/C catalyst (306 mg) was added and the mixture hydrogenated for 1 hour using a Parr apparatus (14 psi). Filtration through Celite and evaporation gave the title compound as a yellow oil. On standing, a pale yellow solid was produced which required no additional purification.
Reaction SMILES: [OH-].[K+].[CH:3]1([CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O.C(O)C>[CH:3]1([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([OH:16])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C1CCCC1
Temperature: -10 °C
Yield: 96 %

Procedure:
KOH (3.42 g, 61.0 mmol) in water (10 mL) was slowly added (over 1 h) to diethyl 2-cyclopentylmalonate (12.12 g, 53.09 mmol) in ethanol (30 mL) at 0° C. The resultant mixture was stirred at 0° C. for 2 h and at rt over night. The mixture was freezing-dried, and the residue partitioned between Et2O and water. The aqueous layer was washed with Et2O. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduce pressure to recover unreacted diethyl cyclopentylmalonate (1.94 g, 8.5 mmol). The aqueous layer was cooled to −10° C. and the pH was adjusted to 1 using HCl (conc.). The water layer was extracted with Et2O (6×50 mL), dried (MgSO4) and concentrated under reduce pressure to give the title compound (10.2 g, 96%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.21-1.38, 1.47-1.75, 1.76-1.97, 2.37-2.55, 3.24, 4.14-4.31. Total no of protons: 15.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[ClH:11]>C1(C)C=CC=CC=1>[Cl:11][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: Cl
Reactant: O=Cc1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
20 g (0.132 moles) of 90 percent pure 4-hydroxymethylbenzaldehyde were stirred for 2 hours at 80° C. under an argon atmosphere with 50 ml of 37 percent HCl (0.58 moles) and 200 ml of toluene. After cooling to room temperature, the aqueous phase was separated off and the toluene phase was evaporated in vacuo. This gave 16.2 g of crude product which, according to NMR, contained 78.8% by weight of 4-chloromethylbenzaldehyde, 10% by weight of 1,4-bis-chloromethylbenzene and 11.2% by weight of an unknown substance. A 4-chloromethylbenzaldehyde yield of 12.8 g, corresponding to 62.5% of the theoretical yield was calculated from the NMR result.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH:22]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>ClCCl>[CH:22]1([N:26]2[CH2:31][CH2:30][N:29]([C:15]([CH:13]3[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:14]3)=[O:17])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC(C(=O)N2CCN(C3CCC3)CC2)C1
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (250 mg, 1.06 mmol) in dichloromethane (2 mL) at RT was added SOCl2 (115 μL, 1.59 mmol). The mixture was stirred for 18 hours before volatiles were removed at reduced pressure. The residue was then dissolved in dichlormethane (3 mL) and 1-cyclobutylpiperazine (115 mg, 1.28 mmol) followed by DIPEA (940 μL, 5.31 mmol) added. The mixture was stirred at RT for 4 hours and then quenched with saturated aq. NaHCO3 (1 mL). The aqueous phase was extracted with dichloromethane (2×5 mL), the organics combined, washed with brine (2 mL), dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (130 mg, 34%), after purification by silica FCC (97.5:2.25:0.25 DCM/MeOH/NH3).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]([O:13][CH2:14][C:15](Cl)=[O:16])(=[O:12])[CH3:11].O>C(Cl)(Cl)Cl>[C:10]([O:13][CH2:14][C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[F:9])=[O:16])(=[O:12])[CH3:11]
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(=O)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (9.5 g, 50.0 mmol) in 150 ml dry CHCl3 was added drop wise acetoxyacetyl chloride (7.5 g, 55.0 mmol) under nitrogen. The mixture was stirred at room temperature for 0.5 h, then water was added and the solution was extracted several times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 2-(4-bromo-2-fluorophenylamino)-2-oxoethyl acetate (15.2 g) as colorless solid in quantitative yield.
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:24])C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:24])[CH2:15][CH2:16]1
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)C1CCC(F)(F)CC1
Yield: 196.8 %

Procedure:
To 32 mg (0.13 mmol) of 1,3-diethyl-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2,4-dione and 38.4 mg (0.13 mmol) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide was added 2.2 mL of anhydrous DCE and 34 mg (0.17 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 2 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by Bond Elut (ethyl acetate to 5% methanol/DCM) to yield 42 mg (60.9%) of 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[1,3-diethyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=3[CH:29]=2)[C:7](=[O:15])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1>CO>[CH3:1][O:2][C:5]1[N:6]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=3[CH:29]=2)[C:7](=[O:15])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1
Reactant: C#CCN1C(=O)COc2ccc(-n3c(Cl)nc(C(F)(F)F)cc3=O)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#CCN1C(=O)COc2ccc(-n3c(OC)nc(C(F)(F)F)cc3=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.08 g of sodium methylate in 10 ml of methanol is added at 20° C. while stirring to a solution of 7.65 g of 6-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)pyrimidinyl]-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one in 300 ml of absolute methanol. A suspension forms during 15 minutes and the temperature rises to 30° C. The reaction mixture is concentrated at 40°-50° C. under reduced pressure and the residue is dissolved in 500 ml of ethyl acetate. The organic phase is washed twice with 200 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The crystalline residue is stirred with 20 ml of diethyl ether, cooled to 0° C. and treated with 100 ml of n-hexane. The crystals are filtered off under suction and dried at 50° C. under reduced pressure. In this manner there is obtained 6-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one, m.p. 218°-220° C.
Reaction SMILES: [CH:1]1([C@H:6]([NH:11][C:12]([O:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[O:13])[C:7]([O:9]C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.C1COCC1>O>[CH:1]1([C@H:6]([NH:11][C:12]([O:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[O:13])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)OC)C1CCCC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)N[C@H](C(=O)O)C1CCCC1
Temperature: 20 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A mixture of methyl (2S)-cyclopentyl[({[(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy}carbonyl)amino]acetate (1.97 g, 5.84 mmol) and LiOH.H2O (0.74 g, 17.51 mmol) in a 1:1 mixture of THF:H2O (60 mL) was heated to 40° C. The solution was stirred for 4 hours, then cooled to 20° C. The THF was removed under reduced pressure, and the residual aqueous solution was extracted with EtOAc. The organic phase was washed with H2O and brine, then dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (1.85 g, 98%) as an oil that was used directly in subsequent steps. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 7.28 (d, J=8.1 Hz, 1H), 5.84-5.71 (m, 1H), 4.98 (d, J=17.4 Hz, 1H), 4.92 (d, J=10.1 Hz, 1H), 4.60-4.52 (m, 1H), 3.78 (t, J=8.0 Hz, 1H), 2.18-2.05 (m, 1H), 2.04-1.94 (m, 3H), 1.91-1.74 (m, 3H), 1.70-1.06 (m, 15H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12.C(N(CC)CC)C.[C:22]([O:26][C:27]([NH:29][C:30]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=NS(C(F)(F)F)(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:43]([O:42][C:40]([N:39]=[C:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[NH:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: Nc1cnn2c1NCC2
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 7-amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole sulfuric acid salt (4.4 g), 4-(dimethylamino)pyridine (244 mg) and triethylamine (8.10 g) in chloroform (45 ml) was added 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (10.18 g). The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 7-[2,3-bis(tert-butoxycarbonyl)guanidino]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (4.6 g) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH:21]3[CH2:22][CH2:23][CH2:24][CH:17]2[C:18](=[CH:26]O)[C:19](=O)[CH2:20]3)(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH:21]3[CH2:22][CH2:23][CH2:24][CH:17]2[C:18]2[CH:26]=[N:5][N:4]([CH2:3][CH2:2][OH:1])[C:19]=2[CH2:20]3)(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NNCCO
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnn(CCO)c1C2

Procedure:
Prepared as described in Example 5 using hydroxyethylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=NC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:39]3[CH:40]=[N:36][CH:29]=[CH:37][CH:38]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCCc1cccnc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3cccnc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(2-bromoethyl)pyridine hydrobromide and isolated as white solid. MS (m/e): 388.3 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=1.[CH:16]1([CH2:22]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[S:11][CH:12]=1
Reactant: OCC1CCCCC1
Reactant: O=C(O)c1cc(Br)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CCCCC1)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of oxalyl chloride (1.4 mL, 16.1 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise to a solution of 4-bromothiophene-2-carboxylic acid (3.08 g, 14.9 mmol) and DMF (0.2 mL) in anhydrous CH2Cl2 (40 mL) over 30 mins. The reaction mixture was stirred at room temperature for 35 min then concentrated under reduced pressure. CH2Cl2 (30 mL) was added to the residue followed by cyclohexylmethanol (1.9 mL, 15.44 mmol) and Et3N (2.5 mL, 17.94 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between EtOAc and aqueous 25% NH4Cl. Organic layer was washed with brine, concentrated under reduced pressure and purified by flash chromatography (2%-20% EtOAc—hexanes gradient) to give cyclohexylmethyl 4-bromothiophene-2-carboxylate as a colorless oil which was directly used in the next step. Yield (3.61 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 25 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-3-methylbenzene. Yield 25%. MS M+H calculated 380.1; found 380.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 uM.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25](Br)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([N:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]2=[O:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: Oc1cc(C(F)(F)F)ccn1
Product: Cc1nc(-n2ccc(C(F)(F)F)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 9 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 2-hydroxy-4-(trifluoromethyl)pyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 9% yield: mp 197-198° C.; 1H NMR (300 MHz, CDCl3) δ 8.93 (d, J=7.8 Hz, 1H), 7.39-7.25 (m, 5H), 7.00 (d, J=0.6 Hz, 1H), 6.57-6.54 (m, 1H), 6.17 (s, 1H), 4.59 (d, J=5.7 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 159.3, 152.4, 141.0, 137.5, 133.1, 128.8, 127.9, 127.8, 124.1, 119.1, 103.0, 44.2, 17.3; MS (ES+) m/z 394.2 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[C:11]([C:26]([F:29])([F:28])[F:27])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:38](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]2)=[C:11]([C:26]([F:28])([F:27])[F:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCCc1nnc(OC2CCNCC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-5-trifluoromethyl-pyridazine dihydrochloride (0.14 mmol, 0.075 g) and aqueous formaldehyde (37%, 0.68 mmol, 0.070 mL) in dry DCM (1.2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.82 mmol, 0.35 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 493 [M+1]; 1H NMR (400 MHz, CD3OD) δ 7.10-7.19 (2H, m), 7.00-7.09 (2H, d), 5.54-5.82 (1H, m), 4.38-4.43 (1H, m), 3.66 (1 h, d), 3.54 (1H, d), 3.10-3.35 (2H, m), 2.89-2.98 (3H, m), 2.64-2.73 (2H, m), 2.58 (1H, d), 2.46 (1H, d), 2.27 (1H, t), 1.96-2.13 (3H, m), 1.78-1.83 (2H, m), 1.14-1.66 (10H, m), 0.77 (3H, t).
Reaction SMILES: Br[CH:2]([CH2:25][CH3:26])[C:3]([N:5]1[C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:7]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[N:6]1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CCCCO>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[C:7]1[CH2:8][C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:3]([CH:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH2:25][CH3:26])=[O:4])[N:6]=1
Reactant: CCC(Br)C(=O)N1N=C(c2cc(F)ccc2F)CC1(C)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CCCCO
Product: CCC(C(=O)N1N=C(c2cc(F)ccc2F)CC1(C)c1ccccc1)N1CCN(C)CC1

Procedure:
A solution of the more polar (lower Rf on silica gel TLC plate) diastereomeric 1-(2-bromobutanoyl)-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazole (1-1, 370 mg, 0.878 mmol, 1 equiv) and 1-methylpiperazine (0.500 mL, 0.536 mmol, 6.11 equiv) in n-BuOH (3 mL) was heated at 100° C. for 20 h. The reaction mixture was cooled and purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between a 1:1 saturated aqueous sodium bicarbonate solution and brine and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 1-(1-{[3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}propyl)-4-methylpiperazine as a diastereomerically pure racemic mixture. The racemic mixture was separated by normal-phase chiral chromatography (ChiralPak AD column: 95% Hex and 5% i-PrOH with 0.1% diethylamine as a modifier) to provide 1-((1S)-1-{[(5S)-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}propyl)-4-methylpiperazine (1-2, more polar enantiomer) as a white foam. 1H NMR (300MHz, CDCl3) δ 7.63 (m, 1H), 7.35-7.19 (m, 5H), 7.07 (m, 2H), 4.37 (dd, 1H, J=9.2, 5.5 Hz), 3.54 (dd, 1H, J=18.6, 3.0 Hz), 3.46 (dd, 1H, J=18.6, 3.0 Hz), 2.73 (m, 4H), 2.41 (m, 4H), 2.26 (s, 3H), 2.07 (s, 3H), 1.80 (m, 1H), 1.58 (m, 1H), 0.86 (t, 3H, J=7.3 Hz). LRMS m/z (M+H) 441.5 found, 441.2 required.