Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:3]1[C:12]([Cl:13])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=1)[C:3]1[C:12]([Cl:13])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1nc2ccccc2nc1Cl
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3ccccc3nc2Cl)cc1

Procedure:
4-[N-Methyl-N-(3-chloro-2-quinoxalinyl)amino]phenol was reacted with ethyl 2-bromopropionate, following essentially the same procedure as that described in Example 1 Part (b), to give ethyl 2-{4-[N-methyl-N-(3-chloro-2-quinoxalinyl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([CH:14]=[O:15])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:15][CH2:14][C@H:12]1[CH2:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11]1
Reactant: O=C[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OC[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In a 50 mL flask with cis-3-benzyloxymethyl-cyclobutanecarbaldehyde (73 mg, 0.36 mmol) inside, dry CH2Cl2 7 mL was added under argon to give a colorless solution. Then this was cooled to −78° C., DIBAL-H (1.0 M in hexane, 0.7 mL, 0.72 mmol) was added drop by drop. This was left stirring at −78° C. and after 3 hr, the reaction was quenched with dry MeOH 0.2 mL. The reaction mixture was allowed to warm up to RT gradually. After 1.5 hr, 2 mL Rochelle salt was added and the mixture was stirred vigorously for overnight. Then the organic phase was separated and washed with brine, dried over MgSO4 and concentrated. Purification by silica gel flash chromatography (Hexane:EtOAc=3:1) yielded cis-1-hydroxymethyl-3-benzyloxymethyl-cyclobutane as a colorless oil (54 mg, 73.4%, Rf=0.17 (Hexane: EtOAc=3:1)). 1H NMR (CDCl3, 300 MHz): δ 1.48-1.61 (m, 2H), 2.10-2.20 (m, 2H), 2.40-2.55 (m, 2H), 3.39-3.41 (d, J=8.0, 2H), 3.54-3.56 (d, J=8.0, 2H), 4.51 (s, 2H), 7.20-7.40 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:26]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:35]4[N:36]=[C:32]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[O:33][C:34]=4[CH3:50])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 78. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, 2H, J=8.30 Hz), 6.75 (d, 2H, J=8.79 Hz), 6.61 (d, 2H, J=8.30 Hz), 6.42 (d, 2H, J=2.44 Hz), 6.33 (dd, 1H, J=8.30, J=2.44 Hz), 5.88 (d, 2H, J=0.98 Hz), 4.11 (t, 2H, J=5.86 Hz), 3.15 (d, 1H, J=13.68 Hz), 3.03 (d, 1H, J=13.68 Hz), 2.93 (t, 2H, J=5.86 Hz), 2.86 (tt, 1H, J=11.72 Hz, J=3.42 Hz), 2.27 (s, 3H), 1.99-1.96 (m, 2H), 1.80-1.75 (m, 2H), 1.71-1.65 (m, 1H), 1.57-1.46 (m, 2H), 1.37-1.33 (m, 1H), 1.32 (s, 3H), 1.29-1.19 (m, 2H); HRMS (ES+) m/z exact mass calcd for C29H34NO7 508.2335, found 508.2351.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]3[N:15]([CH3:18])[N:16]=[CH:17][C:12]3=[C:11]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=2)=[CH:5][CH:4]=1.I[Si](C)(C)C>C(#N)C>[CH3:18][N:15]1[C:13]2=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[N:8][CH:7]=3)=[CH:10][C:11]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:12]2[CH:17]=[N:16]1
Reactant: COc1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cnn(C)c3n2)cn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cn1ncc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(-c3ccc(O)nc3)nc21
Temperature: 70 °C
Yield: 33.7 %

Procedure:
To 6-(6-methoxypyridin-3-yl)-1-methyl-4-(4-(methylsulfonyl)phenoxy)-1H-pyrazolo[3,4-b]pyridine 117 (110 mg) in acetonitrile (1 mL) was added iodotrimethylsilane (1 mL). The reaction mixture was heated at 70° C. for 3 h and purified by reverse phase HPLC to afford 119 (35.8 mg). MS (ESI) m/z 397.1 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:23][CH:22]2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=3[CH:53]=2)=[CH:17][CH:16]=1)=O.B#B.O1CCCC1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:23][CH:22]2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=3[CH:53]=2)=[CH:19][CH:20]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)Cc4ccccc4F)cc3)cc21
Agent: B#B
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNCCc4ccccc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.455 g of benzyl 4-(4-{2-[2-(2-fluorophenyl)acetylamino]ethoxy}phenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 5 ml of tetrahydrofuran is admixed at 0° C. with 1.84 ml of diborane-tetrahydrofuran complex (1M solution in tetrahydrofuran). The reaction solution is subsequently heated to reflux over 3 hours. The reaction solution is cooled to room temperature, quenched with 2 ml of methanol and finally admixed with 2 ml of 2M HCl. The mixture is stirred at room temperature over 30 minutes, neutralized with 20 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 3×20 ml of ethyl acetate. The combined organic phases are washed with 20 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F). Rf=0.52 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.83.
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH2:5]([CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1)[CH:6]=[CH2:7]>O1CCCC1>[CH3:2][C@H:9]1[C@H:8]([CH2:5][CH:6]=[CH2:7])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1
Reactant: C=CCC1C=CC(=O)CC1
Reactant: C[Cu]C
Agent: [Li]
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCC(=O)C[C@H]1C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a 0° C. solution of 0.282 mole of dimethyl copper lithium in 200 ml. of tetrahydrofuran was slowly added a solution of 25.6 g. (0.188 mole) of 4-(2-propenyl)cyclohex-2-en-1-one in 50 ml. of tetrahydrofuran. The reaction was stirred 15 minutes and then quenched by addition to a 0° C. saturated solution (500 ml.) of ammonium chloride. The quenched reaction was extracted with 500 ml. ether. The ether extract was washed with 500 ml. saturated ammonium chloride, dried over magnesium sulfate and evaporated to an oil which was purified via distillation to yield 15.5 g. (55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]#[C:16][C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([F:23])[CH:22]=1.CC(C)([O-])C.[K+].ClCCl.C(OCC)(=O)C>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:24][C:18]2=[N:19][CH:20]=[C:21]([F:23])[CH:22]=[C:17]2[CH:16]=1
Reactant: COc1cc2c(C#Cc3cc(F)cnc3N)cn(C)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc2c(-c3cc4cc(F)cnc4[nH]3)cn(C)c2cc1OC
Yield: 24.2 %

Procedure:
But using 0.19 g of 3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)-5-fluoropyridin-2-ylamine and 0.263 g of potassium tert-butoxide in 15 ml of 1-methylpyrrolidin-2-one. After flash chromatography on a silica column [eluent: dichloromethane/ethyl acetate (90/10 by volume)], 0.046 g of 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH:8]=[N:7][CH:6]=[C:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19]Br.Cl>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][N:9]1[C:4](=[O:3])[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][N:7]=[CH:8]1
Reactant: CCOC(=O)c1cnc[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (0.262 g, 6.54 mmol, 60% dispersion in mineral oil) and ethyl 6-oxo-1,6-dihydropyrimidine-5-carboxylate (1 g, 5.95 mmol) was dissolved in DMF (11.89 ml). After 30 min at room temperature, 3,4-difluorobenzyl bromide (0.761 ml, 5.95 mmol) was added. The reaction mixture was stirred at room temperature overnight and then poured into aqueous hydrochloric acid (10%). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes, to afford ethyl 1-(3,4-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate as an off-white solid. LRMS (EST) calc'd for (C14H13F2N2O3) [M+H]+, 295.1; found 295.1.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25])=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=Cc1ncc(-c2cccc(NCC(=O)OC(C)(C)C)c2)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ncc(-c2cccc(NCC(=O)OC(C)(C)C)c2)cn1
Temperature: 50 °C
Yield: 39.3 %

Procedure:
30 mg of 10% Pd/C are added to a solution of 0.3 g (0.81 mmol, 1 eq) of methyl 3-{5-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrimidin-2-yl}acrylate (obtained as in 9c) in 3 ml of methanol, in a PARR bomb. The reaction mixture is placed under a hydrogen pressure of 3 bar and is then heated at 50° C. for 12 hours. The reaction medium is cooled to room temperature and then degassed with nitrogen and filtered through Celite. After evaporating off the solvents, the residue is chromatographed on silica gel (90/10 heptane/ethyl acetate). 118.2 mg of methyl 3-{5-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrimidin-2-yl}propanoate are obtained in the form of a colorless oil. Yield=40%.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.[H-].C([Al+]C(C)C)(C)C.CO.O>C(Cl)Cl>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([OH:14])[CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: OCCC(O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 5.0 g of ethyl-4-chlorobenzoylacetate in 100 ml of methylene chloride cooled to -30° C., 77.3 ml of diisopropylaluminium hydride (1.0 mol/l toluene solution) was added, and the resulting mixture was stirred for 30 minutes and then brought back to room temperature over 3 hours, and 4.14 g of methanol and 24.3 g of water were added carefully, and the mixture was stirred for another 1.5 hours. The precipitate was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane/ethyl acetate=1/1), to obtain 2.45 g of the title compound as a pale yellow oily substance.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:10]=1[O:11][CH:12]([CH3:16])[C:13]([OH:15])=O.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:37]([O:45][CH2:46][CH3:47])(=[O:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCOCC.C(N(CC)CC)C>[CH2:42]([O:41][C:39](=[O:40])[CH:38]([C:13](=[O:15])[CH:12]([O:11][C:10]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:9]=1[CH3:8])[CH3:16])[C:37]([O:45][CH2:46][CH3:47])=[O:44])[CH3:43]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(Cl)ccc1OC(C)C(=O)O
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Into a 200 ml round-bottomed flask equipped with a magnetic stirrer, a thermometer, a dropping funnel and a calcium chloride tube 100 ml of toluene, 10.1 g of triethyl amine and 21 g of 2-(2'-methyl-4'-chloro-phenoxy)-propionic acid are weighed in. The reaction mixture is cooled under 0° C. and 10.8 g of ethyl chloro formiate are added dropwise at such a rate that the temperature should be between -1° C. and 0° C. The thick suspension formed is stirred for a further period of 20 minutes, whereupon a mixture of diethyl-ethoxy-magnesium-malonate prepared from 17.6 g of diethyl malonate and 50 ml ether is added dropwise at such a rate that the temperature should not exceed 0° C. The reaction mixture is allowed to stand at room temperature for 16 hours and worked up as described in Example 1. Thus 31 g of the desired compound are obtained in the form of a pale yellow oil, yield 88%, nD25 =1.348.
Reaction SMILES: C(O)(=O)C.Cl.Cl.[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>CC(C)=O>[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[O:21])[N:7]([C@@H:8]3[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]3)[C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: N[C@@H]1CCCNC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=O)N([C@@H]1CCCNC1)C2=O
Temperature: 27.5 °C

Procedure:
In a clean round bottom flask, 100 ml acetic acid, 50 gms 3-(R)-aminopiperidine dihydrochloride & 56.5 gms of 4-methylphthalic anhydride were charged. The reaction mass was refluxed & then cooled to 25-30° C. Acetone was added to the reaction mass & obtained solid was filtered. Acetone was added to the solid obtained & refluxed to get uniform slurry. The reaction mass was cooled to 25-30° C. & filtered. Wet wt 70 gms. In another round bottom flask, methylene dichloride, wet cake and water were charged. The reaction mass was basified & layers were separated. The organic layer was washed with water & concentrated upto half volume. Diisopropyl ether was added to the reaction mass to obtain the product. Dry wt 40 gms, HPLC purity=85%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]2[C:15]([CH3:18])=[N:16][NH:17][C:4]=2[CH:3]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:9]1([O:8][C:6]2[C:5]3[C:15]([CH3:18])=[N:16][NH:17][C:4]=3[CH:3]=[C:2]([CH:19]3[CH2:21][CH2:20]3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: Cc1n[nH]c2cc(Cl)nc(OC3CCCCC3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: Cc1n[nH]c2cc(C3CC3)nc(OC3CCCCC3)c12
Yield: 17.8 %

Procedure:
To a microwave tube was added 6-chloro-4-(cyclohexyloxy)-3-methyl-1H-pyrazolo[4,3-c]pyridine (49 mg, 0.18 mmol), cyclopropylboronic acid (80 mg, 0.9 mmol), Pd(dppf)Cl2 (15 mg, 0.018 mmol). The tube was flushed with nitrogen for 2 minutes before adding a 2 M solution of sodium carbonate in water (0.28 mL) and 1,4-dioxane (2 mL). The tube was sealed and irradiated in a microwave at 160° C. for 25 minutes. The reaction mixture was then filtered and concentrated. The crude product was purified by reverse-phase HPLC to give the title compound (8.7 mg, 17%). LC-MS (Method G): m/z=272.1 [M+H]+; 5.44 min. 1H-NMR (400 MHz, DMSO): δ 12.57 (s, 1H), 6.83 (s, 1H), 5.15 (m, 1H), 2.02 (m, 1H), 1.87 (m, 2H), 1.71 (m, 2H), 1.62 (m, 2H), 1.46 (m, 4H), 0.87 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:37])[CH3:36]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:41]2[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][CH2:40]2)=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1
Reaction time: 15.5 h
Yield: 80.5 %

Procedure:
To a solution of E-4-fluorocinnamic acid (1.18 g, 7.10 mmol), which is commercially available from Sigma-Aldrich, and TBTU (3.42 g, 10.6 mmol) in DMF (50 mL) was added 1-isopropylpiperazine (1.12 mL, 7.81 mmol) at ambient temperature. The reaction was stirred for ca. 15.5 h before being concentrated under reduced pressure, wherein the crude residue was dissolved in EtOAc (70 mL) and partitioned with sat. aq. NaHCO3 (25 mL). The aq. layer was separated and further extracted with EtOAc (2×30 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (2×20 mL) and brine (35 mL), then concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2-40 g; gradient elution: 100% DCM for 5 min, then 0% to 2% MeOH/DCM over 5 min; hold for 5 min, 2% to 4% over 5 min, hold for 5 min, 4% to 10% over 5 min, hold 10% MeOH/DCM for 5 min at 40 mL/min) to give 1.58 g 10A (80% yield) as a pale orange solid. m/z (ES+) M+1=277.4; HPLC tR=1.50 min. 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J=15.6 Hz, 1H), 7.50 (dd, J=8.9, 5.5 Hz, 2H), 7.11-6.99 (m, 2H), 6.80 (d, J=15.6 Hz, 1H), 3.85-3.54 (m, 4H), 2.73 (quintet, J=6.7 Hz, 1H), 2.55 (d, J=5.2 Hz, 4H), 1.05 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3](O)=[O:4].S(Cl)(Cl)=O.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([NH:33][C:3](=[O:4])[CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])(=[O:32])=[O:31]
Reactant: CS(N)(=O)=O
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1nn(-c2cc(CC(Cl)C(=O)NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 120 °C
Yield: 33.8 %

Procedure:
In a manner similar to Example 7, the reaction of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound A2) with 5 mL of thionyl chloride produced a residue. To this residue was added 0.50 g (0.0052 mole) of methanesulfonamide. The mixture was stirred and heated at 120° C. for two hours. The mixture was cooled, diluted with methylene chloride, and a resultant precipitate was removed by filtration. The filtrate was washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 0.21 g of N-methylsulfonyl-2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionamide as a foam, Compound A25 of Table 1A.
Reaction SMILES: [C:1](Cl)(=[O:14])[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH3:13].[Cl-].[CH:17]1([O:23][C:24]([C:26]2[N:27]=[C:28]([CH:31]3[CH2:36][CH2:35][NH2+:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C.O>ClCCl>[CH:17]1([O:23][C:24]([C:26]2[N:27]=[C:28]([CH:31]3[CH2:32][CH2:33][N:34]([C:1]([O:2][C:3]4[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=4[CH3:13])=[O:14])[CH2:35][CH2:36]3)[S:29][CH:30]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1ccc(C(F)(F)F)cc1OC(=O)Cl
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(F)(F)F)cc1OC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 2-methyl-5-(trifluoromethyl)phenyl chlorocarbonate (239 mg) is added to a solution of 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (VII-1, 324 mg) and diisopropylethylamine (323 mg) in dichloromethane (8 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulphate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives 2-methyl-5-(trifluoromethyl)phenyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (193 mg, 39%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylsulfamoyl chloride (81 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 77%). 1H NMR (400 MHZ, CDCL3) δ7.19 (D, 2H), 6.93-6.91 (D, 2H), 4.05 (T, 2H), 3.78-3.76 (M, 2H), 3.59-3.54 (M, 2H), 3.17-3.15 (D, 2H), 2.76-2.70 (M, 12H), 2.15-2.06 (M, 4H), 1.90-1.87 (M, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:22]1([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:15])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CCCNC1)N1CCCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To a solution of 1 g 3-(2-phenyl-piperidine-1-carbonyl)-piperidine-1-carboxlic acid tert.-butyl ester in DCM (15 mL) was added 40% trifluoroacetic acid in DCM (6 mL). The mixture was stirred at room temperature for 4-5 h. After completion of the reaction all volatiles were evaporated, water (20 mL) was added and the mixture extracted with (2×25 mL) diethyl ether. The aqueous layer was adjusted with 10% aq. NaOH to pH=12, and extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to yield 0.731 g (95%) of the title compound. (MH+) 273.36.