Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][C:5]=1[O:30]C)([CH3:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[OH:30][C:5]1[CH:6]=[C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)c(O)c1)CO2
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of N-(3-(4-isopropyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.18 mmol) obtained in Example 185 in dichloromethane (5 mL) was added dropwise at −70° C. under an argon atmosphere boron tribromide (1.0 M, dichloromethane solution, 2.36 mL, 2.36 mmol) and the resulting mixture was gradually warmed to room temperature. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 465 mg (yield: 96%) of the title compound. Melting point: 220-221° C. (ethyl acetate-hexane).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:16])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:16][C:6]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2nccs2)CC1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A solution of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.0 g, 4.14 mmol) in 20 mL of THF/3 N HCl (1:1) was stirred for 1 h at 50° C. After cooling to room temperature, the mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.82 g of 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone in 99% yield. MS (EI) calcd: (M+H)+=198.1; found: 198.2.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][C:20]1[NH:21][C:22](=O)[C:23]2[CH:28]=[N:27][N:26]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[C:24]=2[N:25]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][C:20]1[NH:21][C:22](=[S:2])[C:23]2[CH:28]=[N:27][N:26]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[C:24]=2[N:25]=1
Reactant: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1cnn2C1CCCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: S=c1[nH]c(Cc2cccc(Cl)c2)nc2c1cnn2C1CCCC1
Temperature: 0 °C

Procedure:
50 mg (0.23 mmol, 1.5 equiv.) of diphosphorus pentasulfide are added to a solution of 50 mg (0.15 mmol) of 6-(3-chlorobenzyl)-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 1) in 1 ml of pyridine at room temperature, and the mixture is then stirred under reflux overnight. After cooling, the reaction solution is mixed with 10 ml of ice-cold 2.5% strength sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: ClCCl.[CH2:4]([S:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[C:26](=[O:27])[N:25]([CH3:28])[C:24]([CH3:29])=[N:23]3)=[CH:17][C:15]=2[N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>O>[CH2:4]([S:11]([C:12]1[S:13][C:14]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[C:26](=[O:27])[N:25]([CH3:28])[C:24]([CH3:29])=[N:23]3)=[CH:17][C:15]=2[N:16]=1)=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1nn(-c2cc3nc(SCc4ccccc4)sc3cc2F)c(=O)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: Cc1nn(-c2cc3nc(S(=O)Cc4ccccc4)sc3cc2F)c(=O)n1C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
10 mL of dichloromethane was charged with 0.001 mol 1-(2-(benzylthio)-6-fluorobenzo[d]thiazol-5-yl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred for 10 mins and then 0.0011 mol m-chloroperoxybenzoic acid (MCPBA) were added. After stirring at room temperature for 2 hours, the mixture was poured into 30 mL of water, extracted with 15 mL dichloromethane twice. Organic phases were combined and dried over anhydrous sodium sulfate. Filtration and removal of solvent under vacuum gave the title compound as a white solid in a 91% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)CCl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N+:18]3[O-:39])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: [O-][n+]1c(-c2ccccc2)ccc2ccc(-c3nc(C4CCC4)n4ccnc(Cl)c34)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (ice-H2O) solution of 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline (197 mg, 0.48 mmol) in ClCH2CH2Cl (20 mL) was added mCPBA (97 mg, max 0.43 mmol, max. 77% Aldrich) in one portion. The solution was stirred at the temperature for 30 min and then allowed to warm to rt by removing the cooling bath and stirred at rt (2 h). The reaction mixture was again cooled (ice-H2O) and treated with another portion of mCPBA (107 mg, max 0.48 mmol), stirred for 30 min at the temperature and then overnight at rt (15 h). After that time the crude mixture was filtered through hydromatrix (25 mL) pretreated with 2 M aq NaOH (10 mL). The hydromatrix column was washed with DCM (˜100 mL) and the filtrate was concentrated under reduced pressure. The resultant yellow residue was purified by flash chromatography on silica gel (70 g cartridge, 0→0.75→4% MeOH in DCM) to yield 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline 1-oxide as a yellow gum. A cooled (−10° C.) i-PrOH (15 mL) solution of 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline 1-oxide (50 mg) in a Parr bomb was saturated with NH3(g) for 3 min. The vessel was sealed and heated at 100-110° C. (bath temperature) for 2 d. The reaction mixture was then cooled to rt, concentrated under reduced pressure and purified by flash chromatography on silica gel (0-4% MeOH+2%˜6 M NH3 in MeOH. A trituration with hexanes (3×) provided the title material as a bright yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.16 (dd, J=8.2 Hz, 1.8 Hz, 1H), 8.04-7.96 (m, 3H), 7.79 (d, J=8.8 Hz, 1H), 7.57-7.43 (m, 4H), 7.16 (d, J=5.2 Hz, 1H), 7.13 (d, J=4.8 Hz, 1H), 5.30 (s, 2H), 3.85 (quintet, J=8.2 Hz, 1H), 2.69-2.60 (m, 2H), 2.55-2.50 (m, 2H), 2.30-2.15 (m, 1H), 2.15-2.00 (m, 1H); MS (ES+): m/z 408.13 (100) [MH+]; HPLC: tR=2.14 min (OpenLynx, polar—5 min).
Reaction SMILES: C(OC([N:8]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:34]([Cl:35])=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=2)[CH2:22][CH:21]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:35].[Cl:35][C:34]1[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH3:10])[CH:21]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:22]2)=[N:27][CH:28]=[C:29]([CH:33]=1)[C:30]([OH:32])=[O:31]
Reactant: COc1cccc([C@@H](C)N(CC2CCN(c3ncc(C(=O)O)cc3Cl)CC2c2ccccc2)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)NCC2CCN(c3ncc(C(=O)O)cc3Cl)CC2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 142 mg of the crude product of 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and to the obtained residue was added ethanol and ethyl acetate, followed by heating under reflux, and then being left to be cooled to room temperature. Then, the precipitate was collected by filtration, and dried under reduced pressure to obtain 78 mg of 5-chloro-6-[4-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]nicotinic acid hydrochloride as a white solid.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:12].[OH-]>C1COCC1>[O:1]([CH2:8][C:9]([NH2:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)COc1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of phenoxyacetyl chloride (6.18 g, 36.2 mmol) in 175 mL of THF was added 75 mL of NH4OH over 15 minutes. The reaction was stirred for 16 hours at 23° C. then concentrated under reduced pressure. The crude product was dissolved in 200 mL of EtOAc and washed with 100 mL of 2 N HCL, 100 mL NaHCO3, and 100 mL of brine. The organic phase was dried over Na2SO4 and concentrated. The product was purified by recrystallization from EtOAc/hexanes to provide 4.05 g (74% yield) of the desired product as a white powder.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[CH:20][C:19]=1[F:30].CC(=O)OCC>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[CH:20][C:19]=1[F:30]
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1ccc(F)c(Cl)c1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4ccc(F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.7 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (239 mg, 1.0 mmol) and 2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg, 1.07 mmol) in DMF (5 mL) at rt was added TEA (108 mg, 1.07 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound 5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (140 mg; yield 30.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.80-7.70 (m, 4H), 7.64-7.60 (m, 2H), 4.43 (d, J=18.4 Hz, 1H), 4.27 (d, J=18.4 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 96.0% at 220 nm and 96.4% at 254 nm; MS: m/z=428.1 (M+, ESI+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[CH:10]([C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1)=[CH2:11]>>[CH:12]1([CH2:10][CH2:11][CH:3]2[C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C=CC1=CCCCC1
Reactant: CC1(C)C=CC(=O)CC1
Product: CC1(C)CCC(=O)CC1CCC1CCCCC1
Yield: 75 %

Procedure:
Using 4,4-dimethylcyclohex-2-enone (53 μL, 0.40 mmol) as substrate and vinylcyclohexene (0.14 mL, 1 mmol, 2.5 eq) as reagent and following General Procedure 3 overnight gave the above product (72 mg, 0.30 mmol, 75%) as a colourless oil after purification by column chromatography (1:49 EtOAc/petrol). The product compound was characterised using 1H NMR and 13C NMR, IR and MS. The presence of an enantioexcess was determined by derivatization using the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[S:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH:39]3[CH2:40][CH2:41][S:36][CH2:37][CH2:38]3)[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: NC1CCSCC1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NC3CCSCC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.186 mmol) and tetrahydro-2H-thiopyran-4-amine (100 mg, 0.853 mmol) the title compound was obtained as a crude yellow foam and used directly in the next step. MS (ESI): 620.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=1)[CH2:14][OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCc2ccccc2)cc1CO
Yield: 94.8 %

Procedure:
5-Benzyloxy-2-methoxybenzaldehyde (150.4 g) was suspended in methanol (600 ml) and to the gently warmed stirred mixture was added, in portions, sodium borohydride (15.0 g). The methanol was evaporated and the residue partitioned between dichloromethane and water. The organic layer was washed with water, then saturated sodium chloride, dried with anhydrous magnesium sulphate and evaporated to dryness. The residue crystallised from dichloromethane/petroleum spirit (40°-60° ) to give 5-benzyloxy-2-methoxybenzyl alcohol (143.8 g, 95%), m.p. 50°-51°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:16]([CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]([C:36]1[CH:37]=[C:38]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:51][N:50]=[CH:49][N:48]=2)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1F)#[N:35]>CS(C)=O>[C:34]([C:36]1[CH:37]=[C:38]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:51][N:50]=[CH:49][N:48]=2)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12]1[N:16]([CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[N:15]=[CH:14][CH:13]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate, (Preparation 883, 2.20 g, 0.00574 mol), potassium carbonate (1.60 g, 0.0116 mol) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide, (Preparation 68, 2.50 g, 0.00575 mol) were combined in a 50 mL round bottomed flask and the flask was cooled in ice. Dimethylsulphoxide (15 mL) was added and after a few minutes the ice bath was removed and the reaction was stirred at room temperature for 3 hours under nitrogen. The reaction was diluted with water (50 mL) and extracted with tert-butylmethylether (100 mL) and the organic layer was washed with water (30 mL). The organic extracts were dried over anhydrous sodium sulphate, filtered and the solvent removed in vacuo to give the title compound as a white foam (4.76 g).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+]>C1COCC1.O>[CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: CN[C@H]1CC[C@@H](C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
The methyl cis-4-(methylamino)cyclohexanecarboxylate (3 g, 0.0175 mol) from above was dissolved in a THF/H2O (10 mL) mixture and was cooled to 0° C. Next 2 L of a 0.025 M solution of NaOH was added slowly. The mixture was stirred a 0° C. for another 0.5 hour. The mixture was then acidified to pH 7-8 and extracted with ethyl acetate. The water layer was acidified to pH 3-4 and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give 2.49 g (0.016 mol, 90% yield) of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN1CCOCC1.[C:20](Cl)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl>[CH2:23]([O:22][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(O)CCCCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(O)CCCCNC(=O)OCc1ccccc1

Procedure:
To a well stirred mixture of 0.05 moles of ethyl 6-amino-2-hydroxyhexanoate and 100 ml of methylene chloride which has been cooled to 0° to 5° C is added 0.1 moles of N-methylmorpholine followed by 0.055 moles of carbobenzoxy chloride. The reaction mixture is stirred for 1 hour then washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel and elution with methanol/chloroform gives ethyl 6-(benzyloxycarbonylamino)-2-hydroxyhexanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cn1
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) by alkylation with methyl-5-chloropyrazine-2-carboxylate [CAS Reg. No. 33332-25-1]. MS (m/e)=502.0 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.3) (2.0 g, 6.46 mmol) and commercially available 3-bromo-benzene-boronic acid (1.43 g, 7.12 mmol) according to the general procedure IIb. Obtained as a white solid (0.89 g, 32%). MS (ISP) 430.1 [(M+H)+]; mp 148.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=O)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)NC1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(CCNC2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Yield: 33.7 %

Procedure:
Following the procedure of example 40b, N-[1-(4-benzyloxy-phenyl)-piperidin-4-yl]-2-phenyl-acetamide (200 mg) was reduced with LiAlH4 to give [1-(4-benzyloxy-phenyl)-piperidin-4-yl]-phenethyl-amine (65 mg; 34%) as a white solid (MS: m/e=387.3 (M+H+)).
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:11].[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:11][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:10][C:15](=[O:16])[CH2:14][O:13][CH3:12])[C:2]=1[Cl:1])[C:6]#[N:7])=[O:16]
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C#N)cc(NC(=O)COC)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzonitrile (3.34 g) in pyridine (60 ml) is added dropwise methoxyacetyl chloride (4.0 ml) at room temperature. The mixture is stirred at room temperature for 2 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (5.1 g) having the following physical properties.