Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20](F)=[C:21]([CH3:23])[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4C(=O)OC[C@H]4C)c(C)c3)CC2)c(C)c1
Yield: 17.9 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-5-methylpyridin-3-yl)methanone (720 mg) described in Preparation Example 148 and (R)-4-methyloxazolidin-2-one (443 mg) described in Preparation Example 25, the title compound (161 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][O:21]4)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:18]1[CH2:23][C@@H:22]3[CH2:24][C@H:19]1[CH2:20][O:21]3)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3C[C@@H]4C[C@H]3CO4)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1N1C[C@@H]3C[C@H]1CO3)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-chloro-6-(1S,4S)-2-oxa-5-aza-bicyclo [2.2.1]hept-5-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 253.1 ([{37Cl}M+H]+, 26%), 251.1 ([{35Cl}M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18](Br)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH:34][CH3:35]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([N:34]([CH3:35])[CH3:33])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)COc1ccc(Cl)cc1C1c2sc(Br)nc2CCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1nc2c(s1)C(c1cc(Cl)ccc1OCC(=O)O)N(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C

Procedure:
A solution of (±)-2-bromo-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (21 mg, 0.04 mmol, 1.0 eq.) in 2M dimethylamine in THF (0.5 mL) was heated at 80° C. for 18 hours. The reaction mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N[C:13]1C=CC=C(S(O)(=O)=O)[CH:14]=1>>[CH2:13]=[CH:14][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:8]([OH:11])(=[O:10])=[O:9])[CH:2]=1
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: Nc1cccc(S(=O)(=O)O)c1
Product: C=Cc1cccc(S(=O)(=O)O)c1
Yield: 71 %

Procedure:
If instead of aniline-2-sulphonic acid the same amount of aniline-3-sulphonic acid was used, 11.0 g (71%) of styrene-3-sulphonic acid, Na salt, were obtained by the method indicated in Example 15.
Reaction SMILES: [S:1]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]([O:12]C)=O)(=[O:4])(=[O:3])[NH2:2]>C[O-].[Na+]>[O:12]=[C:10]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[S:1](=[O:4])(=[O:3])[NH:2]1
Reactant: COC(=O)c1sccc1S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Product: O=C1NS(=O)(=O)c2ccsc21

Procedure:
32 g (0.145 mole) of methyl 3-sulfamoylthiophene-2-carboxylate (IX) in 145 ml of 1N methanolic sodium methylate solution is refluxed for 18 hours. The methanol is then evaporated off, the residue is taken up in water and a small amount of sodium bicarbonate, and the aqueous phase is extracted with methylene chloride and acidified with concentrated hydrochloric acid, whereupon the product precipitates as crystals which can be reprecipitated from water or ethanol.
Reaction SMILES: [F:1][CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[Cl-].[NH4+:17].[C-:18]#[N:19].[Na+]>N>[NH2:17][C:3]([CH2:2][F:1])([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[C:18]#[N:19]
Reactant: COc1ccc(CC(=O)CF)cc1OC
Reactant: [C-]#N
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(CC(N)(C#N)CF)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 1-fluoro-3-(3,4-dimethoxyphenyl)-2-propanone (31.5 g, 0.149 mol) and ammonium chloride (9.57 g, 0.179 mol) in a solution of 28% aqueous ammonia (170 ml) is added sodium cyanide (8.77 g, 0.179 mol). The reaction mixture is stirred at room temperature under nitrogen for 20 hours. The solid which separates is removed by filtration on sintered glass, and then washed with 28% aqueous ammonia (50 ml). The solid is dissolved in ether (1.3 l) and the solution is washed with water, then with brine, dried (MgSO4), and filtered. Upon concentration of the solvent, 2-amino-2-fluoromethyl-3-(3,4-dimethoxyphenyl)propionitrile crystallizes (21.8 g), m.p. 76° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.532 g (4.5 mmol) 4-aminobenzonitrile is heated for 1.5 h at 90° C. The reaction mixture is then distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 and 25:1). Title compound is obtained after crystallization of the product-containing fractions from dichloromethane and drying under HV (8 h, 90° C.); m.p. 228-230° C.; ESI-MS: (M+H)+=338.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:13]=1C=O>CCN(CC)CC.C(O)=O>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:13]=1[CH2:4][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 120 °C
Yield: 85.4 %

Procedure:
Meldrum's acid (2.06 g, 14.32 mmoles) was added to TEAF (7.05 ml) at ambient temperature under stirring and the reaction mixture was kept under nitrogen atmosphere. After 10 min 2,4,6-trichloro benzaldehyde (3 g, 14.32 mmoles) was added to the reaction mixture. It was then refluxed at 120° C. for 3 hrs. On completion of the reaction, the mixture was cooled at ambient and was poured into ice water (50 ml). Then aq. layer was extracted with ethyl acetate (3×80 ml), the combined organic layer was washed with brine (40 ml) and dried over sodium sulphate. Organic layer was concentrated under vacuum. 3.10 g (86.0% of theory) of 3-(2,4,6-trichloro-phenyl)-propionic acid was obtained in form of a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:23])=[C:20](O)[CH:21]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:23])=[C:18]([CH:17]=1)[O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: Oc1cc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: Clc1ccc(Br)cc1OC1CCNCC1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1 from tert-butyl 4-hydroxypiperidine-1-carboxylate and 5-bromo-2-chlorophenol.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[Li]CCCC.[CH2:21]([O:23][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)[CH3:22].CN(C)P(N(C)C)(N(C)C)=O.I[CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>O1CCCC1>[CH2:21]([O:23][C:24]1[CH2:29][CH2:28][CH:27]([CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:51])([CH3:53])[CH3:52])([CH3:48])[CH3:49])[C:26](=[O:30])[CH:25]=1)[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Reactant: CCOC1=CC(=O)CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC1=CC(=O)C(CCCO[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.9 %

Procedure:
To a lithium diisopropylamide (LDA) solution [prepared from diisopropylamine (3.82 mL, 27 mmol) and nBuLi (7.26 mL of a 2.5M solution in hexanes, 18 mmol) in tetrahydrofuran (THF, 12 mL) at 0° C.] at −78° C. was added 3-ethoxy-2-cyclohexen-1-one (2.64 mL, 18 mmol) in THF (6 mL), dropwise, over 40 min. After stirring for an additional 30 min at −78° C., hexamethyl phosphoramide (HMPA, 3.16 mL, 18 mmol) was added followed by the dropwise addition of 3-iodo-1-tert-butyldimethylsiloxypropane (5.45 g, 18 mmol) in THF (8 mL). The resultant mixture was allowed to warm to rt, stirred for 6 h and then quenched by the addition of water (10 mL). The reaction mixture was then partitioned between dichloromethane (DCM, 100 mL) and sat. NH4Cl (40 mL). The aqueous phase was extracted with DCM (3×50 mL), the organic phases combined and washed with brine (50 mL), dried over anhydrous MgSO4 and reduced to dryness. The resultant syrup was purified by flash column chromatography (hexanes/EtOAc 8/2) to yield 2 as a pale yellow oil (2.92 g, 51.2%). Rf 0.21 (hexanes/EtOAc 8/2); 1H NMR (300 MHz, CDCl3) δ 5.26 (1H, s), 3.83 (2H, q, J=7.0 Hz), 3.59 (1H, t, J=6.5 Hz), 3.58 (H, t, J=6.5 Hz), 2.38 (2H, t, J=6.2 Hz), 2.20-1.99 (2H, m), 1.85-1.35 (5H, m), 1.31 (3H, t, J=7.0 Hz), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 201.6, 176.7, 102.3, 64.2, 63.4, 45.0, 30.5, 28.0, 26.4, 26.0 (x2), 18.4, 14.2, -5.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:5]O.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[N:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[O:16][CH:5]=1)=[O:17]
Reactant: COC(=O)C(CO)NC(=O)c1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2Cl2 at −20° C. was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (anhydrous). Purification was performed by flash column chromatography on silica gel using ethyl acetate in hexanes as eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1 g, 59%) as a yellow solid. 1H NMR (CDCl3) d (ppm): 8.30 (s, 1 H), 8.12 (d, 1 H), 7.98 (dd, 1 H), 7.45 (m, 2 H), 3.96 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O.O>C1(C)C=CC=CC=1>[CH3:9][N:8]([CH3:10])[C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:1]2[C:18]([CH3:19])=[CH:17][CH:13]=[C:14]2[CH3:16])=[CH:3][CH:4]=1)=[O:7]
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(C(=O)N(C)C)cc1

Procedure:
A solution of 26.4 g of 4-amino-N,N-dimethylbenzamide in 500 ml toluene and 60 g acetonylacetone is refluxed for 16 hours under a Dean-Stark water separator. The solution is washed with water and brine, dried over MgSO4, filtered and the solvent evaporated at 60° and reduced pressure. The residue is crystallized from ether-hexane 1:1 to yield 1-(4-dimethylcarbamoylphenyl)-2,5-dimethyl-1H-pyrrole, m.p. 102°-104°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].[OH-].[Na+].C(O)C>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(SCc2ccc(C#N)cc2)cc(C(C)(C)C)c1O

Procedure:
A solution of 2.00 g (8.39 mmole) of the known compound 2,6-di-t-butyl-4-mercaptophenol, 1.65 g (8.39 mmole) of p-cyanobenzyl bromide, 5 ml of 1.68N sodium hydroxide and 75 ml of ethanol was heated at reflux for 48 hours. The reaction mixture was poured into water, and was then extracted with diethyl ether. The ether extract was washed with water, dried with magnesium sulfate and evaporated to give the crude product This material was purified by silica gel chromatography, eluting with 1% ethyl acetate in hexane, followed by recrystallizations from a mixture of ethyl acetate and hexane and from ethanol to give 1.1 g of 2,6-di-t-butyl-4-[(4-cyanophenyl)methylthio]phenol as white needles, m.p. 143°-145° C. Analysis: Calculated for C22H27NOS: %C, 74.7; %H, 7.7; %N, 4.0; Found %C, 75.1; %H, 8.1; %N, 4.1.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C@@:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:22])[CH:3]=1.C([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:6]([SH:36]([C:28]1[CH:29]=[C:30]([CH3:35])[C:31]([CH2:33][OH:34])=[CH:32][CH:27]=1)[C:3]1[C:4](=[O:22])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])([CH3:14])([CH3:8])[CH3:7]
Reactant: O=C1C=C(O)C[C@@](CCc2ccccc2)(c2ccccc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([SH](C2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)C(C)(C)C)ccc1CO

Procedure:
The title compound was prepared as described in General Method 9 using 0.12 g (0.40 mmol) of (S)-4-hydroxy-6-phenethyl-6-phenyl-5,6-dihydro-pyran-2-one (prepared in Example VV), 0.16 g (0.44 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.22 g (1.6 mmol) of K2CO3, and DMF (2 mL). Upon standard work-up, the residue was chromatographed on silica gel, eluting with 4:1 CHCl3 :EtOAc, to give the title compound, m.p. 186°-187° C. 1H NMR (DMSO-d6) δ (s, 9 H), 1.75 (s, 3 H), 2.25 (m, 3 H), 2.55 (m, 1 H), 3.51 (q, partially obscured by H2O, 2 H), 4.32 (br s, 2 H), 4.90 (br s, 1 H), 6.17 (s, 1 H), 7.09 (m, 2 H), 7.15 (m, 1 H), 7.23 (m, 3 H), 7.37 (m, 1 H), 7.44 (m, 4 H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C=O)C>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][S:29]([CH3:28])(=[O:31])=[O:30])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (92 uL, 1.2 mmol) and triethylamine (0.2 mL, 1.5 mmol). The reaction mixture was stirred at 60° C. for 1 h, at 110° C. for 16 h, allowed to cool to room temperature and partitioned between EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 467 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[H][H].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1>O>[CH3:3][O:4][CH2:5][CH2:6][O:7][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][N:12]=1
Reactant: [H][H]
Reactant: COCCO
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOc1cc(C)c([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
60 percent strength sodium hydride suspension was introduced into 10 ml of ethylene glycol monomethyl ether, and the mixture was stirred until the evolution of hydrogen had ceased. 516 mg of 2-chloro-4-methyl-5-nitropyridine are added, and the mixture is stirred at room temperature until the reaction has gone to completion. 20 ml of water are added, and the mixture is extracted with methyl tert-butyl ether. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=1:3). This gives 2-(2-methoxyethoxy)-4-methyl-5-nitropyridine as a colorless oil. C9H12N2O4 (212.21), MS (ESI): 213 (M+H+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH:30]([O:36][CH2:37][CH3:38])[CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][N:3]([CH:4]2[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)[CH3:2])=[CH:24][CH:25]=1)[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Reactant: CNC1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCN(C)C2c3ccccc3CCc3ccccc32)cc1)OCC
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 5-(methylamino)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride(1.8 g, 6.94 mmol), ethyl 3-(4-bromethoxyphenyl)-2-ethoxypropanoate (2.4 g, 6.95 mmol), potassium carbonate (2.9 g, 21 mmol) and dimethylformamide (7 ml) was heated at 100° C. for 5 h. Benzene (200 ml) and water (200 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with benzene/chloroform to give 2.2 g (65%) of the title compound as an oil. RF=0.60 (chloroform/ethanol/ammonia=20:2:0.1)
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([O:18][CH3:19])=[C:14]([CH2:16]O)[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C>CCOC(C)=O.[Pd]>[CH3:19][O:18][C:13]1[C:10]2[CH2:11][CH2:12][NH:6][CH2:7][CH2:8][C:9]=2[S:15][C:14]=1[CH3:16]
Reactant: CCOC(=O)N1CCc2sc(CO)c(OC)c2CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(C)sc2c1CCNCC2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The product of step d) (70 mg, 0.25 mmol) was dissolved in 10 mL EtOAc and treated with 35 mg of 10% Pd/C (wet, Degussa type E101) and stirred rapidly under an atmosphere of H2 for 3 hour. The reaction was filtered and concentrated. The crude residue was dissolved in 1 mL EtOH and treated with 1 mL 40% aqueous KOH. After heating to 80° C. overnight, the reaction was diluted with water and the product was extracted 2× into DCM. The title compound was obtained upon purification by preparative HPLC-MS. 1H NMR (CDCl3) δ 3.69 (s, 3H), 3.21-3.14 (m, 4H), 3.00 (t; J=5.2 Hz, 2H), 2.88 (t, J=5.1 Hz, 2H), 2.29 (s, 3H); MS: ESI (positive): 198 (M+H).
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])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: N#Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3ccc(C#N)cc3)C(C)(C)C2=O)cn1
Temperature: 25 °C
Yield: 30 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) (250 mg, 0.83 mmol), 4-(chloromethyl)benzonitrile (126 mg, 0.83 mmol), and cesium carbonate (536 mg, 1.65 mmol) were stirred in dimethylformamide (4 mL) at 80° C. for 5 hours. The reaction was allowed to cool to room temperature and then filtered. The filtrate was diluted with ethyl acetate (4 mL) and then water (2 mL) was added. The organic phase was collected, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient 10% to 100% methanol in water) and further recrystallized from ethanol. Yield 30%. 1H NMR (DMSO-d6, 400 MHz): . s, 6H), 2.15 (s, 3H), 2.42 (s, 3H), 4.65 (s, 2H), 5.20 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.81 (m, 3H), 8.20 (d, J=0.8 Hz, 1H). MS 419 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM