Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>[Zn].O>[NH:10]([CH:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(NC2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
In a three neck round bottom flask equipped with mechanical stirrer and water condenser, 15.36 gm (0.10 moles) of 4-piperidone hydrochloride monohydrate and 16.43 gm (0.2 moles) of aniline were added. To this mixture, 130 gm (2.0 moles) of zinc and 120 gm (2.00 moles) of 90% acetic acid were added. The reaction mixture was stirred at room temperature for 24 hrs and at 50 to 70° C. for 24 hrs. Water was then added to the reaction mixture and filtered. Crushed ice was added to the filtrate and was neutralized with excess of aqueous sodium hydroxide solution. The crude 4-anilinopiperidine was obtained by filtration.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:15][C:14]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][N:17]1CCCNC[CH2:18]1>>[CH3:16][N:17]1[CH2:4][CH2:3][CH2:2][N:1]([CH2:6][C:7]2[S:15][C:14]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:18]1
Reactant: c1c(CN2CCCC2)sc2c1CNCC2
Reactant: CN1CCCNCC1
Product: CN1CCCN(Cc2cc3c(s2)CCNC3)CC1

Procedure:
The preparation of this amine was carried out in analogy to that described for 2-(pyrrolidin-1-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (TP1 1) employing 1-methyl-1,4-diazepane in step-8.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(I)cc1

Procedure:
A mixture of 4-iodobenzoic acid (5 g) and thionyl chloride (30 ml) was heated at 70°-80° C. for 2 hours. The reaction mixture was cooled, the thionyl chloride evaporated and the resulting oil was azeotroped with toluene to give 4-iodobenzoyl chloride (5.38 g) as a solid which was used without further purification.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C@@H:9]([O:10][CH3:11])[CH2:8][CH2:7][CH2:6][CH:5]=1.C([Mg]Br)C.C(O[C@H:22]1[NH:25][C:24](=[O:26])[C@@H:23]1[C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:28])(=O)C.Cl>O1CCCC1.C(OCCCC)(=O)C>[Si:30]([O:29][C@@H:27]([C@@H:23]1[C@@H:22]([C@H:5]2[CH2:6][CH2:7][CH2:8][C@H:9]([O:10][CH3:11])[C:4]2=[O:3])[NH:25][C:24]1=[O:26])[CH3:28])([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CO[C@H]1CCCC=C1O[Si](C)(C)C
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCCCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@H]1CCC[C@H]([C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
To a solution of 1-trimethylsilyloxy-6-(S)-methoxy-1-cyclohexene (800 mg, 4 mmol) in tetrahydrofuran (5 ml), a tetrahydrofuran solution containing 1 mol/liter of ethylmagnesium bromide was added and stirred at room temperature for 3 days. This mixture was then cooled to 0° C., and a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl)-2-azetidinone (861 mg, 3 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture and stirred at 0° C. for 1 hour. The resultant mixture was subjected to addition of 2N hydrochloric acid and extraction with butyl acetate. The organic phase was washed with a saturated sodium hydrogencarbonate solution and water, and concentrated under a reduced pressure to obtain a crude product of (3S,4R)-3-[(R)-1-((tert-butyldimethylsilyl)oxy)ethyl]-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]azetidin-2-one. The crude product contained 170 mg of the objective β-isomer. The yield was 16%, and the β:α ratio was 90:10.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:42])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([N:39]([CH3:40])[CH3:41])[N:36]=[CH:35][N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:42])[NH:16][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(N(C)C)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (103 mg, 0.4 mmol) and 3-[3-(6-dimethylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K55) (150 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (109 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:35]([CH3:38])(=[O:36])=[O:37])[C:32]=1[O:33][CH3:34])[C:27]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1c(C(C)(C)C)cc(C(=O)Cl)cc1S(C)(=O)=O
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C(C)(C)C)cc(C(=O)N2CSc3ccccc32)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (182 mg) and 37% formalin (87 μL) in the same manner as in Example 1 was dissolved in chloroform (4 mL), and triethylamine (0.29 mL) and 3-t-butyl-4-methoxy-5-methanesulfonylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (246 mg) as a pale yellow amorphous product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](N)[CH:18]=1)[CH3:3].N([O-])=O.[Na+].[I:29]I>CCOCC.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([I:29])[CH:18]=1)[CH3:3]
Reactant: II
Reactant: CCOC(=O)CCCCCCCCCCCc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCCCCCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.8 %

Procedure:
Glacial acetic acid (4 ml) and concentrated HCl (2.5 ml) were added to a 50 ml Erlenmeyer flask containing ethyl-12-(m-aminophenyl)-dodecanoate (3.92 g, 12.28 mmol). The mixture was cooled in a NaCl/ice bath. A cold aqueous solution of NaNO2 (4 ml, 3.1M) was added to the mixture. The reaction was stirred for 40 minutes before a cold aqueous solution of KI/I2 (2.31 g/1.78 g, 7 ml H2O) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Ether was added to the reaction mixture. The ether layer was separated and extracted with H2O, 10% Na2S2O3, H2O, sat. NaHCO3, and brine. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a reddish oil. The crude product was purified by column chromatography (120 g silica gel, hexanes:-ethyl acetate 20:1) to yield a clear oil, compound 6, ethyl-12-(m-iodophenyl)-dodecanoate (5.28 g, 56.8% yield).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:13])[C@H:6]([NH2:12])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:57]=[CH:56][CH:55]=[CH:54][C:25]=1[O:26][C:27]1[CH2:31]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:29](=[O:53])[CH:28]=1>C(#N)C>[CH2:2]([O:4][C:5](=[O:13])[C@H:6]([N:12]1[CH2:31][C:27]([O:26][C:25]2[CH:54]=[CH:55][CH:56]=[CH:57][C:24]=2[Cl:23])=[CH:28][C:29]1=[O:53])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3]
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Reactant: CCOC(=O)[C@H](N)CC(C)CC
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A suspension of (R)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.57 g, 7.50 mmol) in acetonitrile (9 mL) was treated with N,N-diisopropylethylamine (1.62 mL) and stirred at 60° C. for 15 min. At this time the solution was treated with N,N-diisopropylethylamine (1.62 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 2.39 g, 7.49 mmol) in acetonitrile (4 mL) via a dropping funnel and refluxed for 20 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (1.26 g, 46%).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][O:8][C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([CH2:13][CH2:14][CH3:15])[C:10](Cl)=[O:11]>C(#N)C>[CH3:7][O:8][C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([CH2:13][CH2:14][CH3:15])[C:10]([N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1)=[O:11]
Reactant: c1c[nH]cn1
Reactant: CCCC(OC)(C(=O)Cl)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CC#N
Product: CCCC(OC)(C(=O)n1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 20 ml of acetonitrile was added 2.3 g of the sodium salt of imidazole, and 7.0 g of α-methoxy-α-n-propyl-2,4-dichlorophenylacetic acid chloride was then added dropwise at room temperature. The mixture was stirred for 2 hours, poured into 200 ml of ice water and extracted with 300 ml of chloroform. The extract was concentrated under reduced pressure, and the oily product obtained was purified by column chromatography on silica gel to obtain 2.5 g of N-(α-methoxy-α-n-propyl-2,4-dichlorophenylacetyl)imidazole (compound No. 43). m.p. 99°-101° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[C:20]1([C:26]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34]O)[O:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:34][CH2:33][CH2:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:30]=2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: OCCCCc1cc(-c2ccccc2)no1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(CCCCc2cc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.8 %

Procedure:
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.354 mmol) and 4-(3-phenyl-5-isoxazolyl)-1-butanol (77 mg, 0.355 mmol) were dissolved in dry THF (4 ml) under nitrogen. A solution of dibenzyl azodicarboxylate (94%, 224 mg, 0.708 mmol) in dry THF (2 ml) was added. The mixture was cooled to 0° C. and a solution of triphenylphosphine (185 mg, 0.708 mmol) in dry THF (1 ml) was added. The mixture was stirred for 20 min at 0° C. then at room temperature overnight. The mixture was degassed then stirred with morpholine (0.308 ml) and tetrakis(triphenylphosphine)palladium(0) (82 mg) for 4.5 h. A further 60 mg of tetrakis(triphenylphosphine)palladium(0) was added and stirring continued overnight. The reaction was worked up by partition between EtOAc and 2M HCl, the organic phase evaporated and purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1), MeOH and eluting with DCM-MeOH (1:1) containing 5% AcOH. Further purification by MDAP afforded the title compound (56 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=O)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:35])[CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=2)[CH2:24]1>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:35])[CH:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=3)[CH2:24]2)=[O:14])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: COc1ccc2c(c1)CC(N(C)CCCN)CC2
Reactant: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Product: COc1ccc2c(c1)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-])CC2

Procedure:
The title compound here is prepared from 4,5-dimethoxy-2-nitrophenylacetic acid (5.25 g, 0.0217 mol) and 1-amino-3-[N-methyl-N-(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (5.4 g, 0.0217 mol) analogously to Example R(c). Yield: 8.2 g Mp: 116°-118° C.
Reaction SMILES: [C:1]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]2[C:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][C:27]=2[F:39])=[N:17]1.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH2:15][CH:12]3[CH2:13][CH2:14][N:11]3[C:4]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:1]#[N:2])=[O:6])[N:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:28][C:27]=3[F:39])[C:19]=12
Reactant: CC(C)C=C(C#N)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid (30.7 mg, 0.220 mmol), 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (57.5 mg, 0.150 mmol in DCM (2 mL) was added PyAOP (86.2 mg, 0.160 mmol) and TEA (0.06 mL, 0.440 mmol) and the resulting yellow solution stirred at rt for 1 h. LCMS showed that the reaction was complete and the crude mixture was directly loaded onto a silica gel cartridge for purification (3 to 5% MeOH: CH2Cl2). Removal of solvent from cleanest fractions afforded 30 mg of the desired compound 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (30 mg, 0.0586 mmol, 39.8% yield) as judged by LCMS. (M+1=512).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:1](=[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCCC1=Cc1ccccc1
Yield: 25.8 %

Procedure:
A 500-ml four-necked flask equipped with a thermometer was charged with 53 g of benzaldehyde, 25 ml of water and 1 g of sodium hydroxide, to which 68 g of cyclohexanone were added dropwise at 30° C. over 30 minutes. The resultant mixture was stirred for 1 hour at the same temperature. After neutralizing the reaction mixture to separate liquid layers from each other, the resultant reaction product was dissolved in 500 ml of toluene. To the solution, 0.5 g of PTS (p-toluenesulfonic acid) was added to conduct azeotropic dehydration for 3 hours in a 1-liter four-necked flask equipped with a Dean-Stark trap and a thermometer. After cooling, the residue was neutralized and washed with water, and the resultant organic layer was dried and concentrated, thereby obtaining 119 g of a crude product. This product was purified by column chromatography to obtain 24 g (yield: 28%) of 2-benzylidenecyclohexanone.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[NH2:14][CH2:15][CH:16]([Cl:24])[CH2:17]S(C(F)(F)F)=O.FC(F)(F)C(O)=[O:28].NCC(Cl)CS(Cl)(C(F)F)=O.FC(F)(F)C(O)=O.NCC(Cl)CS(Cl)(Cl)(CF)=O>>[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[NH2:14][CH2:15][CH:16]([Cl:24])[CH2:17][S:3]([C:2]([Cl:6])([Cl:5])[Cl:1])=[O:28]
Reactant: NCC(Cl)CS(=O)C(F)(F)F
Reactant: ClSC(Cl)(Cl)Cl
Agent: NCC(Cl)CS(=O)(Cl)(Cl)CF
Agent: NCC(Cl)C[SH](=O)(Cl)C(F)F
Solvent: O=C(O)C(F)(F)F
Product: NCC(Cl)CS(=O)C(Cl)(Cl)Cl

Procedure:
Employing the procedure substantially as described in Example 4, but substituting for the trichloromethylsulfenyl chloride used in Step A thereof, an equimolecular amount of the sulfenyl chlorides of structure RSCl wherein R is F3C--, ClF2C--, and FCl2C--, there are produced respectively: 1-amino-2-chloro-3-(trifluoromethylsulfinyl)propane trifluoroacetic acid salt; 1-amino-2-chloro-3-(chlorodifluoromethylsulfinyl)propane trifluoroacetic acid salt; and 1-amino-2-chloro-3-(dichlorfluoromethylsulfinyl)propane trifluoroacetic acid salt.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:18][O:19][P:20]([O:23]C)[O:21][CH3:22]>>[C:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][P:20](=[O:23])([O:21][CH3:22])[O:19][CH3:18])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COP(OC)OC
Reactant: O=S(=O)(c1ccccc1)c1ccc(CBr)cc1
Product: COP(=O)(Cc1ccc(S(=O)(=O)c2ccccc2)cc1)OC
Yield: 86 %

Procedure:
1-(Bromomethyl)-4-(phenylsulfonyl)benzene (Step 1, 10.1 g, 32.5 mmol) was heated to reflux in trimethylphosphite (40 mL) for 16 hours. The cooled reaction was azeotroped with xylene then purified by flash column chromatography on silica, eluting with ethyl acetate to give dimethyl [4-(phenylsulfonyl)benzyl]phosphonate (9.5 g, 86%). δH (360 MHz, CDCl3): 7.92–7.84 (4H, m), 7.55–7.39 (5H, m), 3.64 (6H, d, J=10.9 Hz), 3.16 (2H, d, J=21.6 Hz).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:31])[C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: CN
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Yield: 85 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with methylamine to give the title compound as a white solid (170 mg, 85%); NMR Spectrum 1.65 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 7.00 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.71 (m, 3H), 8.12 (s, 1H), 8.39 (m, 1H), 8.52 (m, 2H), 9.05 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](I)[CH3:30]>CN(C=O)C.C(OCC)(=O)C>[CH2:29]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:30]
Reactant: CCI
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (Example 5-1b) (160 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. Ethyl iodide (155 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH(aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes). The compound was known to inhibit the hT2R14 with IC50 of 20 μM. Yield 35%. MS M+H calculated 350.11, found 350.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C:8]2[C:9]([CH3:20])=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.Cl[C:24]([O:26][C:27]([CH3:29])=[CH2:28])=[O:25]>N1C=CC=CC=1>[F:22][C:3]1[CH:4]=[C:5]([F:21])[C:6]([C:8]2[C:9]([CH3:20])=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]=1[NH:1][C:24](=[O:25])[O:26][C:27]([CH3:29])=[CH2:28]
Reactant: CNc1cc2nc(C)c(-c3cc(N)c(F)cc3F)cc2cn1
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3nc2C)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Treat a 0° C. solution of 3-(5-amino-2,4-difluorophenyl)-N,2-dimethyl-1,6-naphthyridin-7-amine (1.45 g, 4.83 mmol) in pyridine (30 mL) drop-wise with isopropenyl chloroformate (0.528 mL, 4.83 mmol), warm to RT and stir overnight. Add EtOAc, wash with satd. NaHCO3 (2×), dry, concentrate and purify by silica gel chromatography (EtOAc/TEA pre-wash, EtOAc/Hex) to afford the title compound (1.449 g, 78%). 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.85 (s, 1H), 8.03 (s, 1H), 7.67-7.63 (m, 1H), 7.49 (t, 1H), 6.87-6.84 (m, 1H), 6.52 (s, 1H), 4.73 (s, 1H), 4.70 (s, 1H), 2.82 (d, 3H), 2.38 (s, 3H), 1.91 (s, 3H); MS (ESI) m/z: 385.2 (M+H+).