Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(S(O[CH2:14][C:15]([C:18]2[O:22][N:21]=[C:20]([NH2:23])[CH:19]=2)([CH3:17])[CH3:16])(=O)=O)=CC=1)([O-])=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:16][C:15]([C:18]1[O:22][N:21]=[C:20]([NH2:23])[CH:19]=1)([CH3:17])[CH2:14][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(C)(COS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(N)no1
Reactant: C1COCCN1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(CN1CCOCC1)c1cc(N)no1
Temperature: 140 °C
Yield: 59.2 %

Procedure:
Six equivalent batches of a stirred mixture of 2-(3-aminoisoxazol-5-yl)-2-methylpropyl 4-nitrobenzenesulfonate (50 mg, 0.15 mmol), morpholine (0.016 mL, 0.179 mmol), DBU (0.027 mL, 0.179 mmol) and acetonitrile (0.75 mL) were heated in a microwave reactor at 140° C. for 2.5 h. After cooling to rt, the reactions were combined and concentrated under reduced pressure. The residue was partitioned between chloroform and saturated aqueous sodium carbonate solution. The organic layer was separated and washed with brine. The organic layer was separated and dried over sodium sulfate, filtrated and concentrated under reduced pressure to give the crude product. Purification via silica gel column chromatography (eluting with a gradient of 100% chloroform to 5% methanol in chloroform) afforded 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-amine (20 mg, 10%) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](I)=[CH:6][CH:7]=1.[Cu](C#N)[C:11]#[N:12].[C-]#N.[Na+].[OH-].[NH4+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[N:4][C:3]=1[CH3:9]
Reactant: N#C[Cu]C#N
Reactant: Cc1nc(I)ccc1Br
Agent: [C-]#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(C#N)ccc1Br
Temperature: 80 °C

Procedure:
A 1-L, three-neck, round-bottom flask equipped with a mechanical stirrer and a nitrogen inlet was charged with 3,6-dibromo-2-methylpyridine (150 g, 0.59 mol), copper (I) cyanide (42.8 g, 0.47 mol) and sodium cyanide (23 g, 0.47 mol). To the mixture was added N,N-dimethylformamide (300 mL). The mixture was heated to 95° C. and stirred for 48 h. The reaction mixture was cooled to ambient temperature and poured into ethanol (3 L) while stirring. The mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure and partitioned between water (3 L) and ethyl acetate (3 L). The organic layer was separated and washed with brine (2×600 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel plug purification (0-5% ethyl acetate in hexanes) to afford the product (61.5 g, 45% yield) as a white solid. In addition, 19.32 g (14%) of the mixture of the starting material and the product was isolated. Alternate approach: 3,6-Dibromo-2-methylpyridine (1 equiv) and sodium iodide (2 equiv), were combined in propionitrile (15×vol). The mixture was stirred and iodotrimethylsilane (0.2 eqive) was added. The reaction mixture was heated and stirred at 95° C. for 24 h, cooled to room temperature and diluted with ethyl acetate and water. The organic phase was washed with aqueous sodium bicarbonate, aqueous sodium thiosulfate, and aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure with addition of ethyl acetate to a residue. The product was solidified under vacuum to give 3-bromo-6-iodo-2-methylpyridine as an off-white solid. 3-Bromo-6-iodo-2-methylpyridine (1 equiv) in acetonitrile (7×vol) was treated with copper cyanide (0.5 equiv), sodium cyanide (0.8 equiv), and additional acetonitrile (3×vol). The reaction slurry was heated at 80° C. for 24 h. The reaction mixture was cooled to room temperature, treated with aqueous ammonium hydroxide (1.2 equiv), and filtered through Celite. The filtrate was diluted with ethyl acetate and the phases were separated. The organic layer was washed with aqueous ammonium hydroxide and aqueous sodium chloride, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid.
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH2:13][CH2:14][O:15]C)[CH:6]=1)N.BrCC1C=C(C=CC=1)C#N>C(O)CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]#[N:2]
Reactant: COCCOCc1cccc(C(N)=NO)c1
Agent: N#Cc1cccc(CBr)c1
Solvent: OCCO
Product: N#Cc1cccc(COCCO)c1

Procedure:
The title compound was obtained following procedure described for Intermediate 75 but starting from 3-(bromomethyl)benzonitrile (1 g, 5.1 mmol) and ethylene glycol (10 mL) to give the title compound as a yellowish oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.80 (bs, 1H), 7.76-7.74 (m, 2H), 7.69-7.67 (m, 1H), 7.59-7.53 (m, 1H), 4.68 (t, J=5.4 Hz, 1H), 4.55 (s, 2H), 3.58-3.53 (m, 2H), 3.50-3.46 (m, 2H). HPLC (Method A) Rt 2.31 min (Purity: 83.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([SH:16])[CH2:14][SH:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:17]([C:19]1[C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([CH:26]=1)[CH:24]=O)#[N:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[C:17]([C:19]1[C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([C@H:24]2[S:16][C@H:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:14][S:15]2)[CH:26]=1)#[N:18]
Reactant: COc1cc(C=O)cc(C#N)c1OC
Reactant: COc1cc(C(S)CS)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(C#N)c1OC

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (2.36 g, 9.09 mmole), 5-cyano-3,4-dimethoxybenzaldehyde (49) (1.50 g, 7.85 mmole) and 0.788 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope for 24 hours. The benzene was removed in vacuo, and the remaining oil redissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3 and H2O. The organic layer was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.0 cis/trans ratio (2.91 g, 86%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33]([NH:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([NH:36][CH2:37][C:38]([NH:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(=O)NCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (13 mg, 28 μmol) was dissolved in abs. pyridine (2.0 ml). At room temperature, acetamidoacetyl chloride (8 mg, 57 μmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.6 mg, 65% of theory).
Reaction SMILES: [K+].[C:2]([C:4]1[CH:13]=[C:12]([F:14])[C:7]2[N:8]=[C:9]([S-:11])[S:10][C:6]=2[C:5]=1[F:15])#[N:3].[K].S[C:18]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[F:14][C:12]1[C:7]2[N:8]=[C:9]([S:11][CH3:18])[S:10][C:6]=2[C:5]([F:15])=[C:4]([C:2]#[N:3])[CH:13]=1
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Reactant: N#Cc1cc(F)c2nc([S-])sc2c1F
Agent: [K+]
Agent: [K]
Product: CSc1nc2c(F)cc(C#N)c(F)c2s1

Procedure:
4,7-Difluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile was synthesized as a yellow solid (1.0 g, 37%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-cyano-4,7-difluorobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. 1H NMR (500 MHz, DMSO-d6) δ 8.04 (m, 1H), 2.88 (s, 3H); LCMS (ESI) m/z 243 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]4[NH:38][N:37]=[N:36][N:25]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC#N)c23)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 1.00 g (2.4 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}hexanenitrile, 4.19 g (26.3 mmol) trimethylsilylazide and 0.91 g (3.6 mmol) di-n-butyltin oxide in 50 ml toluene overnight at 80° C. After concentrating by evaporation, take up the residue in water, acidify with dilute hydrochloric acid and extract with methylene chloride. Wash the organic phase with sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 10% acetonitrile, 3-50 min 10%→98% acetonitrile, 50-55 min 98% acetonitrile). Crystallize the combined product fractions from diethyl ether and dry overnight at 50° C. in a vacuum drying cabinet. 598 mg (54% of theor.) of the title compound is obtained as almost white crystals.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].C[O:6][C:7]1[CH2:11][CH2:10][C:9](=O)[C:8]=1[CH3:13].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH:8]([C:9]1[CH2:10][CH2:11][C:7](=[O:6])[C:1]=1[CH3:2])=[CH2:13]
Reactant: COC1=C(C)C(=O)CC1
Reactant: C=C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C)C(=O)CC1
Temperature: 0 °C
Yield: 322.5 %

Procedure:
A one-liter, three-necked flask equipped with a mechanical stirrer, reflux condenser, dropping funnel and nitrogen inlet was flamed out under nitrogen. After 65.6 g (0.05 mole) vinyl magnesium bromide in 500 ml THF was transferred to the reaction flask, 23.3 g (0.18 mole) of 3-methoxy-2-methyl-2-cyclopentenone 7 in 100 ml of dry THF was then added dropwise over a period of several hours. For the reasons supra, methanol with p-toluenesulfonic acid, may be preferred for larger quantity production. The mixture was cooled and then stirred into a four-liter beaker containing 1 kg of cracked ice. After adjustment to pH 3 with concentrated HCl, the reaction mixture was extracted with CHCl3. After washing the combined chloroform extracts with water, the solvent was removed under reduced pressure to give 19.7 g of a yellow liquid. This material was distilled (55°-56° C. at 0.1 mm) to give a 60% yield:nmr (CDCl3) δ7.2-5.2 (m,3, --CH=CH2) and 1.8 (s,3, --CH3).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[OH:16].[BH4-].[Na+]>CO.O.CCOC(C)=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCC(O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.52 ml of 4-tert-butylbenzaldehyde (3.1 mmol) and 320 mg of [rac]-2-amino-1-(4-fluoro-phenyl)-ethanol (2.06 mmol) were dissolved in 15 ml methanol at rt, and after stirring for 5 min at rt, were refluxed for 2 h. After cooling down to rt, 117 mg (3.1 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was stirred with diethylether/heptane, filtered and the solid dried under high vacuo, leading to 410 mg of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine as a white solid (66%). MS (ISP) 302.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=O.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42](OS(C)(=O)=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42]([NH:1][CH:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]2)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A mixture of 1.75 g of tert-butyl 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 1.1 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate is heated at 90° C. for 24 hours. After cooling, the reaction solution is diluted with 200 ml of ethyl acetate, and the resulting solution is washed with 30 ml of 5% aqueous phosphoric acid and water, successively, and dried over anhydrous magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is separated and purified by silica gel colum chromatography (hexane:ethyl acetate=2:1), whereby the first fraction yields 0.8 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(SR)-ethoxycarbonylpentyl]amino-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as a colorless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]=[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:53]=2[NH:52]1>CN(C=O)C>[O:50]=[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58]([C:60]3[CH:61]=[C:62]([NH:66][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=3)=[CH:59][C:53]=2[NH:52]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5[nH]c(=O)[nH]c5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 37.2 %

Procedure:
DIEA (0.0085 mL, 0.049 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.009 g, 0.044 mmol) and HATU (0.019 g, 0.049 mmol) in 0.3 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-phenylamine (0.009 g, 0.044 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.007 g of product in 39% yield: LCMS (ESI) m/z 428 (MH+).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:19][CH:20]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=1)[OH:21])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[CH3:31][S:32]([O:21][CH:20]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=1)[CH2:19][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:10][NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CC(O)c1cc(F)cc(C#N)c1)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H](CC(OS(C)(=O)=O)c1cc(F)cc(C#N)c1)O[Si](C)(C)C(C)(C)C
Temperature: -60 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-(3-cyano-5-fluorophenyl)-4-hydroxybutyl)carbamate (I-10) (5.3 g, 12.1 mmol) in DCM (50 mL) at −60° C. was added TEA (5.1 mL, 36.3 mmol) and MsCl (0.98 mL, 12.2 mmol). The resulting mixture was stirred at −60° C. for 2 hours. The reaction was poured into water, diluted with DCM and washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (3R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-1-(3-cyano-5-fluorophenyl)butyl methanesulfonate (I-11). MS m/z 539.1 (M+23)+. Compound decomposed on standing. Used immediately in next reaction without delay.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NC1CCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Yield: 94 %

Procedure:
In analogy to the procedure described for the preparation of example 4, (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (intermediate A-3 [C]) and ethanesulfonyl chloride gave the title compound as a grey solid in 94% yield. MS: 304.99 (M+H+, 1Br).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:19]3[CH:31]=[CH:30][C:22]4[O:23]C(C)(C)[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[ClH:45]>CO.C1COCC1.CO>[ClH:45].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:19]3[CH:31]=[CH:30][C:22]([OH:23])=[C:21]([CH:20]=3)[C:26]([OH:27])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CCCc3ccccc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(CCCc3ccccc3)c3ccc(O)c(C(=O)O)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 6-[{4-[(4-butylphenyl)ethynyl]benzyl}(3-phenylpropyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (147 mg, 0.26 mmol) in MeOH/THF (9 ml, (2/1)) was added an aqueous solution of NaOH (0.3 mL, 5N). The reaction mixture was stirred at rt for 48 hrs. Then a solution of HCl in MeOH (2.5 mL, 1.25M) was added and the solvents were 5 removed under reduced pressure. The residue was taken up with water (5 mL), extracted with Et2O (2×5 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure. The residue was dissolved in a solution of HCl in Et2O (2 mL, 1N). Evaporation of the solvent gave 60 mg (32%) of the title compound as a brown foam. HPLC, Rt: 4.8 min (purity: 78.1%). LC/MS, M+(ESI): 518.4, M−(ESI): 516.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([N:14]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:25][CH:24]=2)=[CH:29][CH:30]=1
Reactant: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCNCC1
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
4-{[4-(4-fluorobenzyloxy)-phenyl]-(3-methyl-butyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester (If, 1.80 g, 3.82 mmol) was dissolved in CH2Cl2 (12 mL), treated with TFA (12 mL), and stirred for 20 minutes. The reaction was concentrated and placed under vacuum for 20 minutes, then diluted with EtOAc (200 mL), washed twice with saturated sodium bicarbonate solution and once with brine, dried over Na2SO4, and concentrated to give 0.89 g (74%) of the desired product.
Reaction SMILES: [Cl-].[NH4+].Br[C@H:4]1[CH2:8][O:7][C@@H:6]2[C@H:9]([CH3:12])[CH2:10][O:11][C@H:5]12.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O.O1CCCC1.ClCCl.[Zn]>[CH3:20][S:21]([O:11][CH2:10][C@H:9]([C@@H:6]1[CH:5]=[CH:4][CH2:8][O:7]1)[CH3:12])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](COS(C)(=O)=O)[C@@H]1C=CCO1
Reaction time: 19 h
Yield: 158.1 %

Procedure:
A solution of ammonium chloride (154 mg, 2.89 mmol) in water (1.5 mL) then zinc dust (289 mg, 4.44 mmol) were added consecutively to a solution of bromide (92) (prepared as above, assumed to be 2.22 mmol) in tetrahydrofuran (6 mL). The mixture was stirred for 19 hours before filtering the suspension through celite in vacuo. The filter cake was washed with diethyl ether (15 mL). A mixture of brine and 1M hydrochloric acid (1:1, 15 mL) was added to the filtrate then the organic phase separated. The aqueous layer was reextracted with diethyl ether (15 mL) then the combined organic layers were washed with brine (10 mL), then dried (MgSO4), filtered and the majority of solvents removed in vacuo to leave a residue. Dichloromethane (2 mL) was added to the residue followed by triethylamine (0.618 mL, 4.44 mmol) then methanesulfonyl chloride (0.334 mL, 4.44 mmol). The suspension was stirred for 2.25 hours then triethylamine (0.309 mL, 2.22 mmol) and methanesulfonyl chloride (0.172 mL, 2.22 mmol) added. The suspension was stirred for 2.75 hours then triethylamine (0.155 mL, 1.11 mmol) and methanesulfonyl chloride (0.86 mL, 1.11 mmol) added. The suspension was stirred for 50 minutes then diluted with dichloromethane (25 mL), washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and reduced in vacuo to leave a pale yellow oil (724 mg). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 30:70 gave mesylate (93) as a colourless oil (260 mg, 57%).