Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[C:6]([CH2:14]Br)[C:7]([C:10](OC)=[O:11])=[N:8][CH:9]=1>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[CH2:14][N:2]([CH3:1])[C:10](=[O:11])[C:7]2=[N:8][CH:9]=1
Reactant: COC(=O)c1ncc(Br)cc1CBr
Reactant: CN
Solvent: C1CCOC1
Product: CN1Cc2cc(Br)cnc2C1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Methylamine (2M in THF, 9.05 mL) was added to methyl 5-bromo-3-(bromomethyl)picolinate (Example 32, step (i), 1.036 g) in tetrahydrofuran (5 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 70° C. for 30 min. The reaction mixture was cooled and filtered, and the filtrate evaporated to dryness to afford crude product. The crude product was purified by chromatography on silica eluting with ethyl acetate/dichloromethane (5:95 to 100:0). The solid collected during the filtration was dissolved in ethyl acetate and washed with water, extracted with dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and extracted again with dichloromethane. The combined organic extracts were dried over magnesium sulfate, and then combined with the chromatographed material to afford the sub-titled compound (0.372 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: OCc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1cccc(-c2cccc(CO)c2)c1
Temperature: 90 °C
Yield: 104.9 %

Procedure:
3-Hydroxymethylbenzeneboronic acid (1.8 g, 11.8 mmol), 3-bromophenylacetic acid (2.55 g, 11.8 mmol), tribasic potassium phosphate, (7.54 g, 35.5 mmol), DMF (55 ml), and water (20 ml) were degassed under nitrogen in a 250 ml flask fitted with a reflux condenser. Bis[triphenylphosphine]palladium(II) chloride (0.17 g, 0.24 mmol) was added. The mixture was degassed under nitrogen, and heated at 90° C. overnight, then acidified with 2N HCl, mixed with brine (15 ml), and extracted with methylene chloride (3×15 ml). The organic materials were combined, dried (MgSO4), then concentrated under reduced pressure which gave 3.0 g of 3-(3-hydroxymethylphenyl)phenyl acetic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.CCN(CC)CC>C(Cl)Cl>[C:26]1([C:13]2([CH:12]=[O:11])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]3[C:25]2=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCC1(c2ccccc2)c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1(c2ccccc2)c2ccccc2-c2ccccc21
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (5.07 mmol) in CH2Cl2 (10 mL) at -60° C. is added DMSO (10.56 mmol) in CH2Cl2, dropwise under an argon atmosphere. The resulting mixture is stirred at -60° C. for 5 min, and a solution of 9-hydroxymethyl-9-phenylfluorene (4.4 mmol) in CH2Cl2 (2 mL) is then added dropwise over 10 minutes to the reaction mixture. The reaction mixture is allowed to stir at -50° C. for another 15 min after the addition is completed. Et3N (3 mL) is added dropwise and the resulting mixture allowed to warm to room temperature over 30 min. The reaction mixture is quenched with H2O (15 mL). The resulting mixture is extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 layers are washed with brine (1×30 mL), dried (Na2SO4) and concentrated in vacuo to afford the crude aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:11]2[O:12]CC(C)(C)N=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[O:27]C1C=C(CC#N)C=C(CCC)C=1OC>>[CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:11]([OH:12])=[O:27]
Reactant: CCCc1cc(CC#N)cc(OC)c1OC
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Product: COc1ccc(C(=O)O)c(CCc2ccccc2)c1OC

Procedure:
Similarly prepared from the corresponding product of step (a) or (b) were:
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)[N:15]=[C:14]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:13]=2)[CH:7]=1.O.O[Li].O.Cl>C1COCC1.C(O)C>[N:34]1([C:14]2[N:13]=[C:12]([C:8]3[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:40])=[O:2])[CH:11]=[CH:10][CH:9]=3)[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[C:29]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:22][CH2:23]3)[N:15]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: COC(=O)CCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Temperature: 55 °C

Procedure:
To a solution of 3-(3-{2-morpholin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-phenyl)-propionic acid methyl ester in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H2O (10 equivalents) followed by a small amount of ethanol to achieve heterogeneity. Heat the mixture at 55° C. for 2 hours then concentrate under reduced pressure. Add a small amount of water to the residue followed by 10 equivalents of HCl (3M solution). Adjust the final pH to 4 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound. 1H NMR (DMSO-D6): δ 2.58 (t, 2H), 2.89 (t, 2H), 3.29 (br m, 4H), 3.66 (br m, 4H), 3.72 (br m, 4H), 3.79 (br m, 4H), 6.72 (s, 1H), 7.22 (m, 1H), 7.31-7.37 (m, 2H), 7.95 (m, 2H), 8.09 (d, 1H, J=7.87 Hz), 8.54 (d, 1H, J=3.3 Hz).
Reaction SMILES: N[C:2]1[N:18]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](CN3CCNC(=O)C3)[N:4]2N=1.FC(F)(F)C(O)=O.C(OC([N:33]([C:51](OC(C)(C)C)=O)[C:34]1[N:50]=[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([CH2:42][N:43]3[CH2:48][CH2:47][NH:46][C:45](=[O:49])[CH2:44]3)[N:36]2[N:35]=1)=O)(C)(C)C>ClCCl>[NH:4]1[C:5]2=[N:18][CH:2]=[C:51]([NH:33][C:34]3[N:50]=[C:37]4[CH:38]=[CH:39][CH:40]=[C:41]([CH2:42][N:43]5[CH2:48][CH2:47][NH:46][C:45](=[O:49])[CH2:44]5)[N:36]4[N:35]=3)[CH:6]=[C:7]2[CH:8]=[CH:9]1
Reactant: Nc1nc2cccc(CN3CCNC(=O)C3)n2n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2cccc(CN3CCNC(=O)C3)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(Cc2cccc3nc(Nc4cnc5[nH]ccc5c4)nn23)CCN1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97 %

Procedure:
4-((2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazin-2-one. Trifluoroacetic acid (2.55 mL, 33.1 mmol) was added to a stirred solution of N,N-di-tert-butoxycarbonyl-5-((3-oxopiperazinyl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.740 g, 1.657 mmol) in dichloromethane (18.5 mL). The resulting solution was capped and stirred at room temperature for 23 h. Most of the solvent was removed on a rotary evaporator. The residue was loaded onto two 5 g Strata X—C ion exchange columns from Phenomenex. The columns were washed successively with acetonitrile, water, acetonitrile, methanol, and then 10% ammonium hydroxide in methanol. The product came off with the 10% ammonium hydroxide in methanol eluent. The 10% ammonium hydroxide in methanol eluent from both runs was concentrated on a rotary evaporator and dried under high vacuum at 40° C. to give the desired product (0.406 g, 1.649 mmol, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.82 (br s, 1H), 7.43 (dd, J=7.42, 8.59 Hz, 1H), 7.28 (d, J=8.59 Hz, 1H), 6.92 (d, J=7.03 Hz, 1H), 6.03 (s, 2H), 3.94 (s, 2H), 3.21 (br s, 2H), 3.12 (s, 2H), 2.71 (t, 2H); MS (ESI) m/z 247.3 [M+1]+.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[NH2:8][C:9]1[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=1.Cl[C:17]1[C:18]2[N:26]=[C:25](Cl)[CH:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[CH3:7][C:5]1[N:6]=[C:2]([S:1][C:25]2[CH:24]=[CH:23][C:19]3[N:20]=[CH:21][N:22]=[C:17]([NH:8][C:9]4[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=4)[C:18]=3[N:26]=2)[NH:3][CH:4]=1
Reactant: Cc1c[nH]c(S)n1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Cc1cnc(N)cn1
Product: Cc1cnc(Nc2ncnc3ccc(Sc4nc(C)c[nH]4)nc23)cn1

Procedure:
The compound of Example 48 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 2-mercapto-4-methylimidazole, 2-amino-5-methylpyrazine and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C:28]([F:49])([F:48])[C@:29]([C:32]3[CH:37]=[C:36](B4OCC(C)(C)CO4)[C:35]([F:46])=[CH:34][C:33]=3[F:47])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl[C:51]1[O:52][C:53]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:54]=2[N:55]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCCC1.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]([NH:24][C:25]2[O:26][CH2:27][C:28]([F:48])([F:49])[C@:29]([C:32]3[CH:37]=[C:36]([C:51]4[O:52][C:53]5[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:54]=5[N:55]=4)[C:35]([F:46])=[CH:34][C:33]=3[F:47])([CH3:31])[N:30]=2)([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)c(F)cc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5o4)c(F)cc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 50.4 %

Procedure:
In a tube a mixture of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-4-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (intermediate D1.1) (130 mg, 144 μmol), 2,6-dichlorobenzo[d]oxazole (30.4 mg, 159 μmol), and cesium carbonate (188 mg, 576 μmol) in tetrahydrofuran (4 ml) and water (2 ml) was purged with argon for 5 minutes. Thereafter, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (5.88 mg, 7.21 μmol) was added, the tube was sealed and the mixture heated at 80° C. for 16 hours. After evaporation, the residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-4-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (52 mg, 50% yield) was obtained as a pale yellow solid. MS (ISP): m/z=716.1 [M+H]+.
Reaction SMILES: [C@@H:1]([OH:5])([CH2:3][CH3:4])[CH3:2].O[C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>>[C@@H:1]([O:5][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)O
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Product: CC[C@H](C)Oc1cc(C(=O)OC)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D14 (first part of synthesis) from (S)-sec-butanol and methyl 3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzoate (D41).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[S:46]1[CH:50]=[CH:49][N:48]=[C:47]1[C@@H:51]([NH2:53])[CH3:52]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:53][C@H:51]([C:47]2[S:46][CH:50]=[CH:49][N:48]=2)[CH3:52])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](N)c1nccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4nccs4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (29 mg, yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:34]=[CH:33][C:15]([C:16]([N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:25]1[C:23]2[CH2:24][N:18]([C:16]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:34][CH:33]=3)=[O:17])[C:19]3[CH:32]=[CH:31][CH:30]=[CH:29][C:20]=3[S:21][C:22]=2[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
To a solution of 385 mg of 2-chloro-benzoyl chloride in 6 ml of methylene chloride at 0° C. is added 0.6 g of 10-(4-aminobenzoyl)-10,11-dihydrodibenz[b,f][1,4]thiazepine followed by 0.375 ml of triethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1N HCl, 1N Na2CO3, water and dried over MgSO4. The filtrate is evaporated in vacuo to give 0.7 g of yellowish solid which is purified by silica gel chromatography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.3 g of the desired product, m.p. 116°-119° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[C:11]1([CH2:20][C:19](=[O:21])[CH:18]([C:22](=[O:25])[CH2:23][CH3:24])[C:17](=[O:26])[CH2:16]1)[CH2:10][CH2:9]2.[C:27](Cl)(=[O:29])[CH3:28].Cl>ClCCCl.ClC(Cl)C>[C:27]([C:14]1[C:13]([CH3:15])=[C:12]2[C:8]([CH2:9][CH2:10][C:11]32[CH2:16][C:17](=[O:26])[CH:18]([C:22](=[O:25])[CH2:23][CH3:24])[C:19](=[O:21])[CH2:20]3)=[CH:7][C:6]=1[CH3:5])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CCC(=O)C1C(=O)CC2(CCc3cc(C)cc(C)c32)CC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CCC(=O)C1C(=O)CC2(CCc3cc(C)c(C(C)=O)c(C)c32)CC1=O
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of aluminium trichloride (4.8 g, 33 mmol) in 1,2-dichloroethane (80 ml) at 20° C. was added a solution of 5', 7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione (3.2 g, 11 mmol) in dichloroethane (10 ml). A solution of acetyl chloride (1.0 g, 13 mmol) in dichloroethane (10 ml) was added and the mixture was stirred at 20° C. for 12 hours. The solution was poured onto cold dilute hydrochloric acid and then extracted with diethyl ether. The ether layer was separated, dried (MgSO4) and evaporated and the crude product was purified by passage through silica gel eluting with methylene chloride. A mixture of 4'-acetyl-5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione and 6'-acetyl-5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione was obtained as a colourless oil (1.0 g, 29%). Pmr spectrum (CDCl3, δ in ppm): 1.16 (3H, t); 1.9-3.3 (17H, complex m); 3.09 (2H, q); 6.84 (0.6H, s); 6.93 (0.4H, s); 18.26 (1H, s).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)C=C.C[N+]1([O-])CC[O:17]CC1.[CH3:21][C:22]([CH3:24])=[O:23]>O.C(O)(C)(C)C.CC(=O)OCC.O=[Os](=O)(=O)=O>[OH:23][CH:22]([CH2:24][OH:17])[CH2:21][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCOc1ccc(C=O)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-allyloxybenzaldehyde (1.0 g, 6.17 mmol) in acetone (40 mL) and water (5 mL) is added a 2.5% solution of OsO4 in tert. butanol (1.25 mL) followed by N-methyl morpholine-N-oxide (867 mg, 7.4 mmol). The pale yellow solution is stirred at rt for 6 h, diluted with EA (250 mL) and washed with 10% aq. citric acid solution (100 mL) and water (2×100 mL). The washings are extracted with EA (150 mL). The combined organic extracts are concentrated and purified by column chromatography on silica gel to give the title compound (731 mg) as a turbid oil. The title compound reversibly polymerizes upon standing. LC-MS: tR=0.58 min, [M+1+CH3CN]+=238.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[C:6]1([C:12]2([C:28]#N)[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:30]1CCCC1>C1(C)C=CC=CC=1>[C:6]1([C:12]2([C:28](=[O:30])[CH2:1][CH2:2][CH3:3])[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccccc3)CC2)cc1
Reactant: CCC[Mg]Cl
Solvent: Cc1ccccc1
Product: CCCC(=O)C1(c2ccccc2)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 67.5 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
88 ml (176 mmol) of n-propylmagnesium chloride are added to a solution of 30 g (88 mmol) of 4-phenyl-1-(toluene-4-sulfonyl)piperidine-4-carbonitrile in 500 ml of toluene. The reaction mixture is stirred for 6 hours at 65-70° C. and then overnight at room temperature. The reaction is stopped by adding 100 ml of tetrahydrofuran, and is then hydrolysed with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then taken up in diethyl ether and filtered off. 1.38 g of starting material are recovered. The filtrate is concentrated to dryness and then chromatographed on silica gel (eluent: 80/20 heptane/ethyl acetate). 17.8 g of 1-[4-phenyl-1-(toluene-4-sulfonyl)piperidin-4-yl]-butan-1-one in the form of a white powder are obtained in a yield of 50%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:38][CH:37]=2)[C:19](=[O:34])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[NH:3][C:4](=[O:7])[O:5][N:49]=3)=[CH:40][CH:41]=2)[C:19](=[O:34])[C:20]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]([CH3:32])[CH3:33])=[CH:28][CH:29]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.79 g), sodium hydrogen carbonate (1.2 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[2-butyl-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.49 g, 78%) as a colorless solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)CN
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
A solution of isobutylamine (1.10 mL, 11.14 mmol) and pyridine (600 μL, 7.42 mmol) in DCM (60 mL) was treated with 4-(bromomethyl)benzene sulfonyl chloride (2.00 g, 7.42 mmol) and stirred at room temperature for 1.5 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) gave 4-bromomethyl-N-isobutyl-benzenesulfonamide (1.08 g, 48%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 4.50 (s, 2H), 4.43 (t, J=6.4 Hz, 1H), 2.78 (t, J=6.6 Hz, 2H), 1.81-1.65 (m, 1H), 0.88 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 308.0 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22](Cl)[CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O.O>[C:6]([O-:5])(=[O:7])[CH3:27].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([C:20]2[CH:21]=[C:22]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@H](c2cccc(-c3cccc(S(C)(=O)=O)c3)c2)C1
Yield: 99.9 %

Procedure:
To a solution of trans-3-(3-chloro-phenyl)-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and 3-(methylsulfonyl)phenylboronic acid (40.3 mg) in a mixture of DMA/water (1.1 mL, 10:1) was added Cs2CO3 (87.6 mg) and [(t-Bu)2P(OH)]2PdCl2 (POPd) (8.1 mg). The reaction mixture was irradiated with microwave at 90° C. for 10 min, and at 140° C. for 10 and 15 min. Water was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptanelethyl acetate 1:1, and on ISOLUTE Flash NH2, n-heptane/ethyl acetate 3:1) yielded trans-3-(3′-methanesulfonyl-biphenyl-3-yl)-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (33 mg, 49%) as a colorless oil, MS: 509.3 (M+NH4)+.