Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2
Reactant: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9H-purin-6-amine trifluoroacetate salt (0.30 g) was heated with anhydrous potassium carbonate (0.4698 g) in anhydrous DMF (5 mL) at 60° C. for 1 hour. The reaction mixture was cooled to room temperature before 4-(bromomethyl) tetrahydro-2H-pyran (0.1669 g) was added in anhydrous DMF (1 mL). The reaction mixture was then stirred overnight at 50° C. The reaction mixture was quenched into water (20 mL) and extracted into ethyl acetate (20 mL, 3 times).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[O:8][C:7]2[CH2:9][CH2:10][C:11]3[CH2:12][CH:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][C:16]=3[C:6]=2[CH:5]=1.[CH3:21][C:22]([CH3:38])([CH3:37])[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][C:31]([OH:36])=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=2[O:26][N:25]=1>>[CH3:38][C:22]([CH3:37])([CH3:21])[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][C:31]([O:36][CH2:2][CH2:3][C:4]3[O:8][C:7]4[CH2:9][CH2:10][C:11]5[CH2:12][CH:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:16]=5[C:6]=4[CH:5]=3)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=2[O:26][N:25]=1
Reactant: COC(=O)C1C=CC2=C(CCc3oc(CCO)cc32)C1
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Product: CCCc1c(OCCc2cc3c(o2)CCC2=C3C=CC(C(=O)O)C2)ccc2c(CC(C)(C)C)noc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylate and 3-(2,2-dimethylpropyl)-7-(n-propyl)-6-hydroxybenz[4,5]isoxazole as a colorless oil.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Cc1ccc(CCBr)cc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CCN2CCC[C@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (1 g), 4-methylphenethyl bromide (0.72 g) , anhydrous potassium carbonate (1.5 g) and acetonitrile (25 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rbombs, yield 1 g, m.p. 110°-113° C. [α]D25 +14.7 (c 1.0 CH2Cl2).
Reaction SMILES: [OH-:1].[Na+].Cl[O-].[Na+].[CH3:6][C:7]1([CH3:22])[CH2:16][C:15]([CH3:18])([CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:19](=[O:21])C)[CH:13]=2)[O:8]1>O.O1CCOCC1>[CH3:22][C:7]1([CH3:6])[CH2:16][C:15]([CH3:17])([CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:19]([OH:21])=[O:1])[CH:13]=2)[O:8]1
Reactant: [OH-]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Temperature: 65 °C

Procedure:
A solution of 2.0 (50 mmol) of NaOH in 10 ml of water was treated with 50 ml of 10% aqueous sodium hypochlorite solution and then with a solution of 1.04 g (4.31 mmol) of 2,2,4,4-tetramethyl-6-acetylchroman (Compound 46) in 15 ml of dioxane. The mixture was heated at 65° C. for 40 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and then diluted with water. The mixture was then washed with ether and the aqueous layer was treated with sodium metabisulphite until it was negative to the potassium iodide - starch test. The aqueous layer was then acidified with 10% H2SO4 and then extracted with ether. This ether extract was washed with water and saturated NaCl solution and then dried (MgSO4). Solvent was removed in-vacuo and the residue recrystallized from ethyl acetate to give the title compound as a white solid. PMR (CDCl3): & 1.39 (6H, s), 1.40 (6H, s), 1.88 (2H, s), 6.85 (1H, d, J~8.7 Hz), 7.85 (1H, dd, J~8.7 Hz, 2.1 Hz), 8.09 (1H, d, J~2.1 Hz). MS exact mass, m/e 234.1256 (calcd. for C14H18O3, 234.1256).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18](Cl)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18]([C:29]5[CH:30]=[N:25][CH:26]=[N:27][CH:28]=5)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(CN1CCc2cc(Cl)nnc2C1)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(CN1CCc2cc(-c3cncnc3)nnc2C1)N1CCN(C2CCC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 7-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-3-chloro-5,6,7,8-tetrahydropyrido-[3,4-c]pyridazine (22 mg, 0.06 mmol), 5-pyrimidineboronic acid (12 mg, 0.09 mmol), Pd(PPh)4 (5.5 mg) and Na2CO3 (28 mg, 0.18 mmol) in DME (3 mL) and water (1 mL) is heated overnight at 80° C. Water is added and the mixture is extracted with DCM. The combined organic layers are dried (MgSO4) and solvent is removed in vacuo to give the crude product, which is purified by PTLC (4% TEA in EA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 9.40 (2H, s), 9.36 (1H, s), 7.64 (1H, s), 4.18 (2H, s), 3.84 (4H, m), 3.48 (2H, s), 3.84˜3.16 (4H, m), 2.56-2.64 (1H, m), 2.04-2.20 (4H, m), 1.60-1.98 (6H, m); MS (+VE) m/z 394.2 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C@@H:22]2[CH2:24][C@H:23]2[C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)C(=O)C(F)(F)F)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C@@H:22]2[CH2:24][C@H:23]2[C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:32][CH:33]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc([C@@H]2C[C@H]2N(CC2CCN(Cc3ccccc3)CC2)C(=O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc([C@@H]2C[C@H]2NCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a solution of 4-(trans-2-(N-((1-benzylpiperidin-4-yl)methyl)-2,2,2-trifluoroacetamido)cyclopropyl)benzoic acid (18 mg, 0.039 mmol) in methanol (1 mL) was added sodium hydroxide (1M, 0.5 mL, 0.500 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified using reverse-phase HPLC under the acidic conditions. The fractions containing the product were combined, treated with 1N HCl, and concentrated. The residue was dried under vacuum to give 9 mg of product (HCl salt) as off white solid. MS: (M+H)+=365.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.50 (q, 1H), 1.59-1.77 (m, 3H), 2.14 (br. s., 3H), 2.63-2.74 (m, 1H), 3.03-3.26 (m, 5H), 3.55 (br. s., 2H), 4.36 (s, 2H), 7.32 (d, J=8.34 Hz, 2H), 7.49-7.62 (m, 5H), 7.99 (d, J=8.34 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=O.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C@@H:24]([NH2:26])[CH3:25])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C@@H:23]([C:27]2[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=2)[C:33]#[N:34])[C@@H:24]([NH:26][CH:5]([C:4]2[CH:3]=[C:2]([F:1])[CH:12]=[C:11]([F:13])[CH:10]=2)[CH2:7][C:8]#[N:9])[CH3:25])=[CH:20][CH:21]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: N#CCC(=O)c1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(CC#N)c1cc(F)cc(F)c1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1

Procedure:
This compound was synthesized according to the procedure of Example 33 from 205 mg (1.13 mmol) of 3,5-difluorobenzoyl-acetonitrile and 300 mg (0.93 mmol) of 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride. LC-MS: m/e=450 (M+1), 452 (M+3) (3.55 min).
Reaction SMILES: [Cu](C#N)[C:2]#[N:3].[F:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[C:10](I)=[C:11]([CH3:13])[CH:12]=1>CN(C)C=O>[F:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[C:10]([C:2]#[N:3])=[C:11]([CH3:13])[CH:12]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1I
Solvent: CN(C)C=O
Product: Cc1cc(F)cc([N+](=O)[O-])c1C#N
Temperature: 130 °C

Procedure:
Copper cyanide (11.9 g, 133 mmol) was added to an N,N-dimethylformamide (240 ml) solution of 5-fluoro-2-iodo-1-methyl-3-nitrobenzene (I-262) (34.0 g, crude product), followed by heating at 130° C. for 3.5 hours. After cooling, the insoluble matter was removed by filtration under suction, water was added to the filtrate, and the precipitated insoluble matter was removed by filtration through Celite under suction. The filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, then the residue was subjected to column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain the entitled compound (17.6 g, 81% from I-235) as a red brown solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[O-:7][CH2:8][CH3:9].[Na+]>C(OCC)(=O)C.C(O)C>[CH:4]1([C:2](=[O:3])[CH2:1][C:8](=[O:7])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC[O-]
Reactant: CC(=O)C1CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)CC(=O)C1CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 8.4 g (0.1 mol) of cyclopropyl methyl ketone in 100 mL of ethyl acetate under nitrogen was added dropwise 39 mL (0.1 mol) of a 21 wt % solution of sodium ethoxide in absolute ethanol. The flask was fitted with a condenser and Dean-Stark trap and was heated. The ethanol was removed by azeotropic distillation. Additional ethyl acetate was added to the flask as needed. After three hours the temperature of the distillate had reached 75° C. and the reaction was allowed to cool and stand overnight. The white solid which precipitated out was collected by filtration and the filtrate was set aside. The solid was dissolved in water and this solution was acidified at 0° C. with 10% aqueous hydrochloric acid. This solution was extracted three times with ethyl ether. The ethyl acetate filtrate was washed with water three times, acidified with 10% aqueous hydrochloric acid, and extracted with ethyl ether. The ether extracts from both extractions were combined, dried over magnesium sulfate, and filtered. Removal of solvents gave 3.5 g of 1-cyclopropyl-1,3-butanedione as an oil. Analysis by GC showed 75% purity. This intermediate was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]2=[CH2:13].[H][H]>C(OCC)(=O)C>[CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH:6]2[CH3:13]
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CC1=C2CCC(=O)CC(C)C2CC1

Procedure:
528 mg of 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 20 ml of ethyl acetate with the aid of 200 mg of palladium-on-calcium carbonate (5%). After hydrogen untake was completed the mixture was filtered off from the catalyst, the filtrate concentrated under reduced pressure and distilled. There was obtained pure 1,4-dimethyl-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene, b.p.0.06 60°; IR(film):νmax = 1700, 1450, 1378, 1250, 1190 cm-1. The compound has a woody, earthy, camphorous odour.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:17](=[O:29])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].O>CN(C)C=O>[N:30]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:17](=[O:29])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:31]=[N-:32]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
2-[(4-{5-Oxo-4-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2,4-oxadiazol-3-yl}-1,2,5-oxadiazol-3-yl)amino]ethyl methanesulfonate (1.2 g, 2.9 mmol) was dissolved in N,N-dimethylformamide (2.7 mL). After sodium azide (280 mg, 4.3 mmol) was added in one portion, the temperature was brought to 65° C. and the reaction stirred for 6 hours. After cooling back to room temperature, water (10 mL) was added to quench the reaction. The product was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo to give the desired product (1.05 g, 96%). LCMS calculated for C13H10F3N6O3 (M−N2+H)+: m/z=355.0. 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.93 (m, 2H), 7.79 (t, J=8.2 Hz, 1H), 6.75 (t, J=5.8 Hz, 1H), 3.52 (t, J=5.7 Hz, 2H), 3.44 (q, J=5.5 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1>>[C:32]([O:31][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:4]2[C:5]3[C:10](=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)[C:2]([CH3:1])=[CH:3]2)=[CH:18][CH:19]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc2[nH]cc(C)c2c1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: COC(=O)c1ccc2c(c1)c(C)cn2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 2, Example 38, using the methyl 3-methyl-1H-indole-5-carboxylate instead of the methyl 1H-indole-5-carboxylate, and the tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate instead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 456 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[I-].C[N+]1C=CN([C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[O:2][C:16](=[O:25])[N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ncccn1
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncccn1)c1ccccc1
Yield: 11.6 %

Procedure:
A solution of 2-hydroxypyrimidine hydrochloride (0.40 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.83 ml, 6.00 mmol) in acetonitrile (15 ml) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate) followed by crystallisation from ethyl acetate:heptane yielding the title compound (0.08 g, 12% yield) as a white solid.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Reactant: CCCCC1CCNCC1
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 74.8 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.105 g, 0.304 mmol) and 4-butyl-piperidine (0.052 g, 0.369 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 3 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM43-40) (0.082 g, 75%). 1H NMR (CDCl3) δ 7.34 (d, J=9.1 Hz, 1H), 7.25-7.17 (m, 2H), 7.02-6.95 (m, 1H), 4.15-3.99 (m, 2H), 3.35 (s, CH2), 2.83 (bd, J=10.4 Hz, 1H), 2.68 (bd, J=10.4 Hz, 1H), 2.20-2.05 (m, 2H), 2.00-1.85 (m, 2H), 1.82-1.73 (m, 1H), 1.67-1.55 (m, 2H), 1.30-1.14 (m, 9H), 0.88 (t, J=7.2, CH3), 0.82 (d, J=6.5 Hz, CH3); 13C NMR (CDCl3) δ 166.0, 139.2, 128.8, 127.1, 124.8, 123.5, 118.9, 63.8, 55.5, 54.4, 47.7, 36.6, 36.1, 32.9, 32.8, 32.1, 29.4, 29.3, 23.2, 16.7, 14.4; HPLC-MS (ammonium acetate) [M+H]+=361.3.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@:19]([CH3:25])([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C@:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:25])[CH:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)[C@](C)(N)CO
Product: CC(C)[C@@](C)(CO)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (2S)-2-amino-2,3-dimethyl-1-butanol (CAN 956102-64-0) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2175 (M+H)+.
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>[Zn].C(OCC)(=O)C>[F:8][CH:2]([CH:23]([OH:24])[CH:20]1[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)Br
Reactant: CCCC1CCC(C=O)CC1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC1CCC(C(O)C(F)C(=O)OCC)CC1
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 1.7 g of well-dried zinc, 3.6 g of ethyl bromofluoroacetate (e-2) and 10 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 2.0 g of 4-propylcyclohexane carboaldehyde (e-8) and 10 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 100 ml of 1 N HCl aqueous solution and 100 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. Then, the resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 3.8 g of ethyl 2-fluoro-3-hydroxy-3-(4-propylcyclohexyl)propanoate (e-9) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34]([OH:36])=O>>[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34]([N:14]([CH:13]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([C:16]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3([CH3:29])[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:12]1)[CH3:15])=[O:36]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-bromo-4-chlorobenzoic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a colorless oil. MS m/e: 656.0 [M]+.