Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15](=O)[C:14]3=[CH:18][C:19]([CH3:21])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:22]=1.CN(C)C1C=CC=CC=1>C1(OC)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]=[C:15]([Cl:3])[C:14]3=[CH:18][C:19]([CH3:21])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:22]=1
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1NC2=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: COc1ccccc1
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Temperature: 82.5 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Under a N2 atmosphere add phosphoryl chloride (124 g, 819 mmol) to a mixture of 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (100 g, 405 mmol), N,N-dimethylaniline (138 g, 1.14 mol) and anisole (550 mL). Heat to 80-85° C. and stir for 4 hr. to 6 hr. Concentrate to a total of 1.5 volumes to 2.5 volumes while maintaining the temperature below 75° C. Cool to 15-25° C. Add dichloromethane (600 mL) dropwise and stir for 1 hr. Add the resulting mixture to water (600 mL) while maintaining the temperature between 10° C. and 35° C. Stir for 1 hr. and then separate the layers. Extract the aqueous layer with dichloromethane (600 mL). Wash the combined organic layers with 1.0 N HCl (600 g) followed by 7% NaHCO3 (600 g). Filter the organic layer through diatomite (20 g to 30 g) and silica gel (60 g to 100 g). Concentrate the resulting filtrate to a total of 1.5 volumes to 2.5 volumes while maintaining the temperature below 45° C. Add heptane (270 g to 410 g) and concentrate the resulting filtrate to a total of 1.5 volumes to 2.5 volumes while maintaining the temperature below 45° C. Add heptane (150 g to 210 g), cool to 5° C. to 10° C., and stir for 2 hr. to 3 hr. Filter, rinse the filter the cake with heptane, and dry under vacuum, at below 45° C., to obtain the title compound as a pale yellow solid (90% to 95% yield)
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:5]=1[C:6]([NH:8][CH:9]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH:26]2[CH2:28][CH2:27]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:7]>CC(C)=O>[I-:2].[CH:26]1([CH2:25][S:22]([C:19]2[CH:18]=[CH:17][C:16]([CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:4]=3[Cl:3])[C:10]3[CH:11]=[N+:12]([CH3:1])[CH:13]=[CH:14][CH:15]=3)=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH2:27][CH2:28]1
Reactant: CI
Reactant: O=C(NC(c1ccc(S(=O)(=O)CC2CC2)cc1)c1cccnc1)c1ccc(Cl)cc1Cl
Solvent: CC(C)=O
Product: C[n+]1cccc(C(NC(=O)c2ccc(Cl)cc2Cl)c2ccc(S(=O)(=O)CC3CC3)cc2)c1
Product: [I-]

Procedure:
Methyl iodide (263 μL, 4.2 mmol) and 2,4-dichloro-N-[{4-[(cyclopropylmethyl)sulphonyl]phenyl}(pyridin-3-yl)methyl]benzamide (prepared as described in Example 53, 200 mg, 0.42 mmol) were stirred in acetone (4 mL) for 16 h under nitrogen. The resulting yellow suspension was concentrated in vacuo to give 3-{{4-[(cyclopropylmethyl)sulphonyl]phenyl}[(2,4-dichlorobenzoyl)amino]methyl}-1-methylpyridinium iodide. The salt was dissolved in methanol (5 mL) and the solution cooled to −10° C. Sodium borohydride (18 mg, 0.47 mmol) was added and the mixture was stirred at −10° C. for 10 mins and then allowed to warm to room temperature, with stirring, over 1 h. The reaction was quenched with 1N NaOH(aq) (20 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated. Purification by chromatography on silica eluting with 5% methanol in dichloromethane (+<0.5% ammonia) was followed by salt formation by treatment with ethereal HCl to give the title compound as a white solid (123 mg, 55% yield). m/z (ES+) 495 (M+H), 493 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2=[CH:6][N:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:4]2[C:3]=1[C:19](O)=[O:20].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:31]([O:30][C:28]([N:22]1[CH2:27][CH2:26][N:25]([C:19]([C:3]2[C:4]3[C:5](=[CH:6][N:7]=[C:8]([O:10][CH3:11])[CH:9]=3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]=2[Cl:1])=[O:20])[CH2:24][CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1cc2c(C(=O)O)c(Cl)n(-c3ccccc3)c2cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1cc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude compound of step 4, tert-butyl 1-piperazinecarboxylate (565 mg, 3.03 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (581 mg, 3.03 mmol) and 1-hydroxybenzotriazole hydrate (312 mg, 2.29 mmol) in DMF (20 ml) was added NMM (911 μl, 8.27 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)C=Cc1ccc2ccccc2c1
Yield: 88 %

Procedure:
The procedure described in Example 28 is repeated, except that 9.55 g (0.05 mol) of 2-naphthoyl chloride and 6.25 g (0.0625 mol) of ethyl acrylate are used. After a reaction time of 2 hours at 120° C., 9.9 g (0.044 mol) of ethyl β-(2-naphthyl)-acrylate are obtained, corresponding to a yield of 88% of theory; boiling point 106°-110° C./4 Pa. Analysis for C15H14O2 (molecular weight 188): calculated C 79.62%, H 6.24%, O 14.14%; found C 79.39%, H 6.49%, O 14.08%.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.Cl.O1CCOCC1>CO>[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C@@H:4]3[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C[C@H]3CCCC[C@@H]32)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1C[C@H]2CCCC[C@@H]2N1C1CCNCC1
Temperature: 25 °C

Procedure:
tert-butyl 4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]piperidine-1-carboxylate was dissolved in MeOH (25 mL) and 4M HCl/dioxane (5 mL) was added. The mixture stirred at room temperature then concentrated in vacuo to give the tile compound. MS (M+1): 223.26
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:22])=[C:14]([F:21])[C:15]4[N:16]=[C:17]([CH3:20])[O:18][C:19]=4[C:11]=3[N:10]([S:23]([CH:26]3[CH2:28][CH2:27]3)(=[O:25])=[O:24])C2=O)=[C:4]([F:30])[CH:3]=1.[Li+].[OH-].FC1C2N=COC=2C(NS(C2CC2)(=O)=O)=C(NC2C=CC(I)=CC=2F)C=1F>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:12]2[C:13]([F:22])=[C:14]([F:21])[C:15]3[N:16]=[C:17]([CH3:20])[O:18][C:19]=3[C:11]=2[NH:10][S:23]([CH:26]2[CH2:28][CH2:27]2)(=[O:24])=[O:25])=[C:4]([F:30])[CH:3]=1
Reactant: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)C1CC1)c(=O)n3-c1ccc(Br)cc1F
Agent: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2c(F)c(F)c(Nc3ccc(Br)cc3F)c(NS(=O)(=O)C3CC3)c2o1

Procedure:
Compound 1H was prepared from 6-(4-bromo-2-fluoro-phenyl)-8-cyclopropanesulfonyl-4,5-difluoro-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-26a: 100 mg, 0.2 mmol) and LiOH (50 mg, 1.25 mmol) in water (2 mL) using procedures analogous to those described above for Compound 1A to afford 30 mg of the product (31.57% yield). H1NMR (CDCl3, 300 MHz): δ 7.30-7.24 (m, 1H), 7.11 (dt, 1H), 6.56 (s, 1H), 6.54-6.46 (m, 1H), 6.33 (s, 1H), 2.70 (s, 3H), 2.68-2.60 (m, 1H), 1.24-1.16 (m, 2H), 1.04-0.96 (m, 2H). LCMS: 95.35%, m/z=474.0 (M-2). HPLC: 93.89%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[CH3:27][C:28]1[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:33]([C:31]3[O:32][C:28]([CH3:27])=[CH:29][CH:30]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: Cc1ccc(C=O)o1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)c1cnc(N)c(N)c1
Product: COC(=O)c1cc(N)c2nc(-c3ccc(C)o3)nn2c1

Procedure:
The title compound, MS m/e (%): 273.2 (M+, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene-sulfonylhydroxylamine, and 5-methylfuran-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([O:24][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Oc1cccnc1
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1cccnc1
Yield: 69.6 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (404 mg), which is obtained in a similar manner to that described in Reference example 39(a), 3-hydroxypyridine (227 mg), triphenylphosphine (938 mg) and solution of diethylazodicarboxylate in toluene (40%, 0.65 ml) and the reaction mixture was treated to afford the desired compound (345 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:31][CH2:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: NCC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNCC2CCCCC2)cc1
Yield: 71.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-((cyclohexylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), cyclohexylmethanamine (0.120 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.061 g (71%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH3:25].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:24]([O:26][C:27](/[CH:28]=[CH:29]/[C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:23])=[CH:10][CH:9]=1)[CH:12]=[C:13]2[C:21]#[N:22])=[O:30])[CH3:25]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(Br)ccc32)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)c(C#N)cn2-c1ccc(C(=O)O)cc1
Yield: 35.9 %

Procedure:
A solution of 4-(5-bromo-3-cyanoindol-1-yl)benzoic acid ethyl ester (0.1 g), acrylic acid ethyl ester (0.11 g) and triethylamine (0.082 g) in N,N-dimethylformamide (2 mL) was stirred in the presence of palladium (II) acetate (0.0061 g) and triphenylphosphine (0.014 g) at 100° C. for 30 hours. This reaction mixture was poured into water, and this resulting mixture was extracted with ethyl acetate twice. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90-75/25) to give the title compound (0.035 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22]([O:27][CH2:28][CH3:29])(=[O:26])/[CH:23]=[CH:24]/[CH3:25].CCN(CC)CC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](/[C:24](/[CH3:25])=[CH:23]\[C:22]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: C/C=C/C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(/C)c1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 10-3 (500 mg, 1.4 mmoles), ethyl crotonate (1.7 mL, 3.8 mmoles), Pd(OAc)2 (31 mg, 0.14 mmoles), NEt3 (0.78 mL, 8 mmoles), tri-o-tolylphosphine (170 mg, 0.56 mmoles), and CH3CN (7 mL) was heated in a sealed tube at 100° C. for 24 hours. The cooled reaction mixture was diluted with EtOAc and then washed with H2O, 10% KHSO4, saturated NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave 12-1 as a waxy yellow solid. Rf 0.33 (silica, 25% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-])=O)[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>C(O)C.O>[NH2:38][C:34]1[CH:33]=[C:32]([C:25]2[N:26]=[C:27]3[N:31]([C:24]=2[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C@@H:13]4[CH2:14][CH2:15][CH2:16][N:11]([S:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)(=[O:10])=[O:9])[CH2:12]4)[N:23]=2)[CH:30]=[CH:29][S:28]3)[CH:37]=[CH:36][CH:35]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-nitrophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (1.05 g, 1.76 mmol) was dissolved in ethanol 95% (10 ml) and water (2.5 ml). The solution was treated with irn powder (1 g, 17.6 mmol) and concentrated HCl (200 uL). The reaction mixture was stirred at 100° C. for one hour. The mixture was cooled down and diluted with ethanol (100 ml). The heterogenous mixture was filtered over Celite and the volatiles were removed in vacuo. The residue was taken up in EtOAc (150 ml) and the organic phase was washed with a saturated aqueous NaHCO3 solution (2×100 ml), water (100 ml) and a saturated aqueous NaCl solution (100 ml). After drying over sodium sulfate and concentration, the solid was triturated in ether, giving the title compound as a yellow powder, 0.835 g (84%). M.p.=226-228° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.73 (br. s, 1H), 8.10 (d, J=5.6 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.36 (d, J=4.4 Hz, 1H), 7.09 (t, J=7.7 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.81 (s, 1H), 6.69 (d, J=7.6 Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.49 (d, J=5.3 Hz, 1H), 5.01 (br. s, 2H), 4.02-3.88 (m, 1H), 3.73 (dd, J=11.1, 3.5 Hz, 1H), 3.47 (d, J=11.7 Hz, 1H), 2.60-2.46 (m, 1H), 2.39 (t, J=10.2 Hz, 1H), 1.98-1.80 (m, 2H), 1.68-1.51 (m, 1H), 1.47-1.32 (m, 1H). LCMS: 566 [M+H]. Calc. for C26H24N7O2S2Cl: C, 55.16; H, 4.27; N, 17.32. Found C, 54.98; H, 3.85; N, 17.23.
Reaction SMILES: [NH2:1][C:2]1[CH:47]=[C:46]([N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:45]=[CH:44][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]=2)[N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=1)=[O:5].[CH3:55][S:56]([Cl:59])(=[O:58])=[O:57].Cl>ClCCl.N1C=CC=CC=1.O1CCOCC1>[ClH:59].[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:44]=[CH:45][C:46]([N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)=[CH:47][C:2]=1[NH:1][S:56]([CH3:55])(=[O:58])=[O:57]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NS(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (29 mg, 0.04 mmol) in anhydrous dichloromethane (2 mL) and dry pyridine (0.05 mL), methanesulfonyl chloride (14.7 mg, 0.01 mL, 0.13 mmol) was added and the reaction mixture was stirred at room temperature for 8 hours. The mixture was poured into ice and was extracted with dichloromethane. The organic layer was washed with 0.1N HCl, then with water, dried over anhydrous Na2SO4 and concentrated to yield a crude whitish solid that was suspended in dioxane (1 mL). After adding 4M HCl in dioxane (0.1 mL) the suspension was stirred overnight. After concentration the residue was suspended in diethyl ether/MeOH 1:1, stirred for 20 min., filtered, washed with the same solvent mixture and dried. The desired product was obtained as the hydrochloride (15 mg, 0.025 mmol, 63%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][CH:6]([CH3:11])[CH2:7][C:8](=[O:10])[CH3:9]>C(O)(C)C>[CH3:5][CH:6]([CH2:7][C:8](=[O:10])[CH2:9][CH:2]([CH3:4])[CH3:1])[CH3:11].[CH3:5][C:6]([CH3:7])=[CH:1][C:2](=[O:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CC(=O)CC(C)C
Solvent: CC(C)O
Product: CC(=O)C=C(C)C
Product: CC(C)CC(=O)CC(C)C
Yield: 2 %

Procedure:
Per hour, 1.5 liters of acetone were passed by the trickle method, i.e. from above, through this tubular reactor, which was at 150° C. and under a hydrogen pressure of 25 bar. This speed corresponds to a mean residence time of about 2 hours, within which an acetone conversion of 38% was achieved. The yield of 4-methylpentan-2-one, based on material converted, was 91%; in addition, 1% of isopropanol, 3% of the double-sided aldolization product 2,6-dimethylheptan-4-one and 2% of 4-methylpent-3-en-2-one were formed. Since the last-mentioned compound is an intermediate of 4-methylpentan-2-one and can be recycled to the synthesis reaction, in order to undergo hydrogenation, the yield of desired products totalled 92%. The conversion and yields were determined by gas chromatography.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C@@H:7]1[C@@H:11]([CH3:12])[O:10][C:9](=[O:13])[NH:8]1>N1C=CC=CC=1>[Cl:3][CH2:6][C@@H:7]1[C@@H:11]([CH3:12])[O:10][C:9](=[O:13])[NH:8]1
Reactant: C[C@H]1OC(=O)N[C@@H]1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H]1OC(=O)N[C@@H]1CCl
Temperature: 25 °C

Procedure:
Thionyl chloride (5.07 ml, 69.4 mmol) was added to a mixture of (4R,5R)-4-(hydroxymethyl)-5-methyloxazolidin-2-one (1.82 g, 13.88 mmol) in pyridine (35 mL) at 0° C. and the mixture was allowed to warm to room temperature for one hour. The mixture was then heated to 60° C. for one hour, allowed to cool to room temperature and then concentrated under reduced pressure. The crude oil was purified by column chromatography on silica to afford (4S,5R)-4-(chloromethyl)-5-methyloxazolidin-2-one. 1H NMR (500 MHz, CDCl3) δ 6.23 (s, 1H), 4.50 (qd, J=6.3, 4.6 Hz, 1H), 3.74-3.63 (m, 1H), 3.59-3.48 (m, 2H), 1.48 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>O.[Cl-].[Zn+2].[Cl-]>[C:1]([C:4]1[O:5][C:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccco1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(=O)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
A mixture of 9.2 g (83.4 mmol) of 2-acetylfuran, 20 ml (2.0 eq) of 4-fluorobenzylchloride and 22.8 g (2.0 eq) of zinc chloride were stirred at 25° C. for 20 hours. The stirring gradually became difficult due to the precipitate. The mixture was dissolved in water and extracted with ethylacetate. The organic layer was washed with water and a diluted sodium hydrogencarbonate aqueous solution and dried over sodium sulfate. The solvent was removed under deduced pressure. A fractional distillation under reduced pressure of the residue gave 9.6 g of 2-acetyl-5-(4-fluorobenzyl)furan. Yield: 53%. 2 mmHg/120-125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:47]=[CH:46][C:38]([CH2:39][NH:40][C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:47]=[CH:46][C:38]([CH2:39][NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])=[CH:37][CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Br)cc1)C1CC1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1)C1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (93.8 mg, 0.21 mmol), cyclopropanecarboxylic acid 4-bromo-benzylamide (50.6 mg, 0.20 mmol), and Pd[P(Ph)3]4 (13.7 mg, 5.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 15.0 mg. MS: 498.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.61-0.79 (m, 4H), 1.56-1.69 (m, 3H), 2.11-2.35 (m, 1H), 3.38-3.59 (m, 2H), 4.25-4.43 (m, 3H), 4.89-5.15 (m, 2H), 7.00-7.65 (m, 12H), 7.85-7.95 (m, 1H), 8.51-8.63 (m, 1H), 10.07-10.16 (s, 1H).
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]=[CH:25][C:24]=1[O:29][CH3:30]>>[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]=[CH:25][C:24]=4[O:29][CH3:30])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1ccccc1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 33 %

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)-2-methoxybenzene (199 mg, 1 mmol). Yield: 33%. MS M+H calculated 396.1; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.