Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1)C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:22]1C=CC(CC(O[Si](C(C)(C)C)(C)C)C)=CC=1>>[Si:1]([O:8][CH:9]([CH3:22])[CH2:10][C:12]1[CH:13]=[CH:14][C:15]([B:18]([OH:19])[OH:20])=[CH:16][CH:17]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(B(O)O)cc1
Reactant: CC(Cc1ccc(Br)cc1)O[Si](C)(C)C(C)(C)C
Product: CC(Cc1ccc(B(O)O)cc1)O[Si](C)(C)C(C)(C)C
Yield: 54 %

Procedure:
According to the procedure for the preparation of 73D, 77B (2.14 g, 6.50 mmol) afforded 1.04 g (54%) of 77C as a colorless solid. MS (ESI) m/z 295.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([I:15])[C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].C([O-])(O)=O.[Na+]>C(OC(C)(C)C)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([I:15])[C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([O:10][C:4]([CH3:11])([CH3:5])[CH3:3])=[O:9])[NH2:7]
Reactant: N[C@@H](Cc1cc(I)c(O)c(I)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cc(I)c(O)c(I)c1
Yield: 148.7 %

Procedure:
A solution of 5.0 g of 3,5-diiodo-L-tyrosine and 0.95 mL of 70% aqueous HClO4 in 155 mL of tert-butyl acetate was stirred at RT under nitrogen for 4 days. The solution was neutralized by addition of 150 mL of 5% aqueous NaHCO3 and the mixture was subjected to rotary evaporation to remove tert-butyl acetate. An off-white precipitate resulted which was collected by filtration and dried in vacuo. The crude product was subjected to flash chromatography on silica gel (97:3 CH2Cl2:MeOH) to afford 4.2 g (75%) of tert-butyl 3,5-diiodo-L-tyrosinate as a white powder, m.p. 165-168° C.
Reaction SMILES: [CH3:1]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:35][CH2:34]3)=[N:29][NH:28][C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CI>CC#N.C(Cl)Cl>[CH:19]1([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[O:45][CH3:46])[CH2:37][CH2:38]3)=[N:29][N:28]([CH3:1])[C:27]2=[O:47])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: COc1ccccc1N1CCN(CCc2n[nH]c(=O)n2CC2CCCCC2)CC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CI
Product: COc1ccccc1N1CCN(CCc2nn(C)c(=O)n2CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a slurry of PS-BEMP (0.95 g, 2.08 mmol, 2.2 mmol/g) and 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (E17; 415 mg, 1.028 mmol) in MeCN (20 mL), methyl iodide (0.13 mL, 2.08 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. The resin was filtered, washed with MeOH (25 mL) and the solvent was evaporated in vacuo to afford 560 mg crude yellow glassy solid. This was dissolved in DCM (3 mL) and purified by flash chromatography (Flash Master, Biotage Isolute SI, 20 g column, gradient 0-10% MeOH in DCM over 30 min) to afford 350 mg of a light yellow oil. Further purification by preparative LC-MS afforded 190 mg (44%) of the title compound as a glassy solid.
Reaction SMILES: [NH2:1][OH:2].Cl.[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](=O)[CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1.N1C=CC=CC=1>CO>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](=[N:1][OH:2])[CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)CCO2
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NO)c1ccc2c(c1)CCO2
Temperature: 20 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
NH2OH.HCl (7.3 g, 105 mmol) was added to a stirred solution of ketone 191 (14.2 g, 87.7 mmol) and pyridine (9.2 mL, 114 mmol) in MeOH (100 mL) and the mixture stirred at 20° C. for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1-(2,3-dihydro-1-benzofuran-5-yl)ethanone oxime (15.3 g, 99%). HCl gas was bubbled through a solution of the oxime (15.3 g, 86.5 mmol) in Ac2O (16.3 mL, 173 mmol) and HOAc (54 mL, 865 mmol), and the solution stood at 20° C. for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2×50 mL), the combined organic extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 192 (7.94 g, 52%) as a white solid: mp 92-93° C. [lit. (Blade-Font, A.; de Mas Rocabayera, T. J. Chem. Soc. P1, 1982, 814848) mp 93° C.]; 1H NMR δ 7.47 (br s, 1H, H-4), 7.21 (br s, 1H, NH), 6.99 (dd, J=8.5, 2.1 Hz, 1H, H-6), 6.69 (d, J=8.5 Hz, 1H, H-7), 4.55 (t, J=8.7 Hz, 2H, H-2), 3.18 (br t, J=8.7 Hz, 2H, H-3), 2.13 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][NH2:4].C(#N)CCCCC.CI.[NH2-].[Na+]>O.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]#[N:4]
Reactant: CCCCC(C)(C)CN
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: Cc1ccccc1
Product: CCCCC(C)(C)C#N
Yield: 81 %

Procedure:
2,2-Dimethylhex-1-ylamine. A solution of capronitrile (25 g., 0.26 mole) and methyl iodide (75 g., 0.53 mole) in 80 ml. of dry toluene is warmed to 80° and treated gradually with a suspension of sodium amide (25.4 g., 0.65 mole) in 100 ml. of toluene at a rate sufficient to maintain general reflux. After addition is complete, the mixture is stirred and refluxed for an additional 2 hr. period, cooled and treated with 150 ml. of water. The organic layer is separated, washed with water and dried over magnesium sulfate. Concentration of the dried solution under reduced pressure and distillation of residual material affords an 81% yield of 2,2-dimethylcapronitrile.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:13]([O:15]C)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[O:15])[CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C=NCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC(Cc2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccccc1

Procedure:
Benzyl isocyanate (1.2 g, Aldrich) was added at room temperature to a stirred solution of the product from step (b) (2.03 g) in toluene (25 ml). When addition was complete, the mixture was refluxed for 40 hours. The toluene was evaporated in vacuo and the residue flash chromatographed through a silica column using chloroform to give the desired product as a colourless oil which crystallised on standing (2.9 g). The product was recrystallised from IPA as fine white needles (1.8 g), mp 92°-93° C. The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[CH3:12][O:13]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([N:37]1[CH2:42][CH2:41][CH2:40][C:39]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)([CH:43]=O)[CH2:38]1)(=[O:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.Cl>[C:34]([N:37]1[CH2:42][CH2:41][CH2:40][C:39]([CH2:43][CH:12]=[O:13])([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)[CH2:38]1)(=[O:36])[CH3:35]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1CCCC(C=O)(Cc2ccc(C)cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)N1CCCC(CC=O)(Cc2ccc(C)cc2)C1
Reaction time: 0.25 h
Yield: 82.7 %

Procedure:
Under an atmosphere of N2, lithium bis(trimethylsilyl)amide solution (10.6 ml, 10.6 mmol, 1.0M in THF) was added dropwise to a solution of methoxy methyltriphenyl phosphonium chloride (3.64 g, 10.6 mmol) in 15 ml THF at 0° C. After 15 min, this solution was added to a solution of the product of STEP 5 (1.95 g, 7.08 mmol) in 15 ml THF at 0° C. The reaction was stirred for 1 h and quenched with H2O. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with H2O, brine, dried with Na0.2SO4, filtered and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH=95/5/0.1) to yield an oil. It was dissolved in 40 ml THF and 40 ml 1.0 N aqueous HCl solution. The reaction was stirred at 25° C. for 2 h. Potassium carbonate powder was added to neutralize the reaction mixture. The solvent was evaporated and residue was extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, and concentrated to give 1.6 g of product. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.N1C=CC=CC=1.[CH:36]([S:39](Cl)(=[O:41])=[O:40])([CH3:38])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[S:9]([N:7]1[CH2:6][CH2:5][N:4]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=2)[C@@H:3]([CH2:2][NH:1][S:39]([CH:36]([CH3:38])[CH3:37])(=[O:41])=[O:40])[CH2:8]1)(=[O:10])=[O:11]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)S(=O)(=O)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.5 %

Procedure:
To a solution of 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (108 mg, 0.240 mmol) in CH2Cl2 (3 mL) was added pyridine (50 μL, 0.618 mmol, Sigma-Aldrich, St. Louis, Mo.) followed by isopropylsulfonyl chloride (27.0 μL, 0.240 mmol, Sigma-Aldrich, St. Louis, Mo.). After stirring at room temperature for 12 h, Hünig's base (0.5 mL) and more isopropylsulfonyl chloride (27.0 μL, 0.240 mmol) were added. The mixture was then heated at 60° C. for 12 h. MeOH (2 mL) was added and the mixture was concentrated. The residue was partitioned between CH2Cl2 and saturated aqueous NH4Cl. The organic layer was concentrated and purified on silica gel (1 to 4% MeOH in CH2Cl2) then by preparative TLC (1 to 4% MeOH in CH2Cl2) to give N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2-propanesulfonamide (10 mg) as a mixture of two isomers.
Reaction SMILES: C([Li])CCC.[CH3:6][CH:7]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH:7]([CH2:8][CH2:9][CH3:10])[CH3:6])[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC(C)OC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(C)OC1CCC(=O)N1C(=O)c1ccccc1
Yield: 65.3 %

Procedure:
12.4 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.2 g of 5-(2-pentyloxy) pyrrolidin-2-one in 130 cm3 of tetrahydrofuran. The mixture is maintained at this temperature for 20 minutes, then a solution of 2.62 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The solution is returned to ambient temperature, concentrated and chromatographed on silica (eluent: hexane-ethyl acetate 7-3). 3.35 g of expected product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.ClC[CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: ClCCCSc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCSc1ccccn1
Yield: 57.3 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) is dissolved in acetone (50 ml). To the solution are added 2-(3-chloropropyl)thiopyridine (2.0 g) and potassium carbonate (1.5 g) and the mixture is refluxed for 4 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol and the product is recrystallized from ethanol to obtain 1-methyl-5-[2-(2-pyridyl)thioethyl]thio-1,2,3,4-tetrazole (1.5 g) as colorless prisms, m.p. 77°-79.5° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[C:13]([CH:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=O)[CH3:14]>C(O)(=O)C.O.CO>[CH3:14][C:13]1[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([CH3:25])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: CC(=O)C(C)CCCCCC(=O)O
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCCC(=O)O

Procedure:
To a stirred solution of 4-hydrazinobenzenesulfonic acid (Aldrich, 11.25 g, 0.06 mol) in acetic acid (50 ml) was added 7-acetyloctanoic acid (16.7 g, 0.09 mol). The reaction mixture was heated under reflux for 12 hrs. Acetic acid was removed under reduced pressure. The resulting solid was dissolved in methanol and reprecipitated with a saturated solution of potassium hydroxide in isopropanol. The solid was filtered, washed with isopropanol and dried, (8 g, 40%). The analytical sample was obtained by C18 reversed phase column chromatography using water/methanol mixture as solvent., m.p. 250° C. dec; IR νcm−1=2930, 2597, and 1719. 1H NMR, D2O, δ, 7.8-7.9 (m, 2H, 4-H and 6-H of aromatic protons); 7.6 (d, J=7 Hz, 1H, 7-H of aromatic); 2.2 (t, J=7 Hz, 2H, —CH2—COOH); 1.9-2.1 (m, 2H, alkyl); 1.2-1.6 (a singlet merged in a multiplet, 7H, —CH3 & (—CH2)2); 0.6-0.9 (m, 2H, alkyl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:10][CH3:11])=[CH:5][O:6][CH2:7][CH2:8][Cl:9].[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH2:10][CH3:11])[CH2:5][O:6][CH2:7][CH2:8][Cl:9]
Reactant: CCC(=COCCCl)C(=O)OC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCC(COCCCl)C(=O)OC
Yield: 82 %

Procedure:
37 g of 3-(2-Chloroethoxy)-2-ethylacrylic acid methyl ester (0.192 mole) was dispersed in 350 ml ethanol together with 6 g Raney nickel catalyst. The mixture was hydrogenated in a pressure vessel at 55°-60° C. at a hydrogen gage pressure of 30-60 atmospheres. When no further hydrogen was absorbed, the contents of the vessel were filtered to remove the catalyst, the solvent was distilled off, and the residue was fractionated in a vacuum. 3-(2-Chloroethoxy)-2-ethylpropionic acid methyl ester was obtained in an amount of 30.7 g (33.7 g) as a fraction boiling at 110° C. and 14 torr (82%-90% yield). nD20 =1.4399, d420 =1.083.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[S:7][C:6]=2[CH:13]=1.[N+:16]([O-])([OH:18])=[O:17]>C(OCC)(=O)C.ClCCl>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[S:7][C:6]=2[C:13]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1cc2cc(C(=O)O)sc2cc1O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2cc(C(=O)O)sc2c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Hydroxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid (3.2 g) was dissolved in ethyl acetate (200 ml) and a solution of nitric acid in dichloromethane (2M, 7.7 ml) was gradually added at 0° C. into. The solution was stirred 30 min at room temperature and then it was poured into ice-cold water and filtered. The solid was washed with ethyl acetate and dried under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:24].O>CN(C=O)C.[Cl-].[Na+].O>[O:24]=[C:19]1[C:18]([O:10][C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21][NH:20]1
Reactant: CCOC(=O)C1(Cl)CCCNC1=O
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCNC1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a mixture of 3,4,5-trifluorophenol (14.4 g) and potassium carbonate (40.3 g) in DMF (200 mL) was added ethyl 3-chloro-2-oxopiperidine-3-carboxylate (20 g), and the mixture was stirred at 100° C. for 1 hr. To the reaction mixture were added water (200 mL) and saturated brine (200 mL) at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL), water (200 mL) and saturated brine (200 mL×2), and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (24.61 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.C([SiH](CC)CC)C>C1C=CN=CC=1.F>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: CC[SiH](CC)CC
Agent: F
Solvent: c1ccncc1
Product: Brc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of 5-bromo-2,3-dihydro-1H-inden-1-one (4.74 mmol) in HF-pyridine (5 mL) in a 100 mL Nalgene round bottomed flask was cooled to 0° C. and treated with triethylsilane (11.85 mmol) over a period of 5 min. The reaction solution was allowed to warm to room temperature and was stirred for 3 h. Analysis by LCMS indicated only partial conversion of the starting material, so the reaction contents were cooled to 0° C. and treated with more triethylsilane (11.85 mmol). The reaction solution was allowed to warm to room temperature and was stirred for 2 days. The reaction was quenched with 50 mL of ice water and after one hour was further diluted with an additional 50 mL of water. The mixture was extracted with dichloromethane. The resulting organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexanes) to afford the title compound as a clear oil (65%). 1H NMR (400 MHz, CDCl3) δ ppm 7.35 (s, 1H) 7.23 (d, J=2.02 Hz, 1H) 7.08 (d, J=8.08 Hz, 1H) 2.79-2.96 (m, 4H) 2.05-2.11 (m, 2H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[N+]([C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1)([O-])=O>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:17]3[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.00 g, 0.019 mol) in N,N-dimethylformamide (50 mL) was reacted with 60% sodium hydride in oil (0.92 g, 0.023 mol) at ambient temperature. The mixture was stirred for 15 minutes, and 4-nitropyridine-N-oxide (5.37 g, 0.038 mol) was added. The mixture was heated at 100° C. for 18 hours. The precipitate which formed was filtered, washing with N,N-dimethylformamide and ethyl acetate to give 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (3.79 g, 0.011 mol) as a tan solid:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][C:19](=[O:20])[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(CBr)N1CCc2ccccc2C1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCc3ccccc3C2)cc1
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.582 g) in dimethylformamide (8 mL) under argon was treated with 55% sodium hydride (0. 141 g), stirred for 30 minutes and then 2-(2-bromo-1-oxoethyl)-1,2,3,4-tetrahydroisoquinoline (0.762 g) in dimethylformamide (6 mL) was added. The solution was stirred at room temperature for 20 hours and worked up as in Example 20. The crude product was purified by HPLC (ethyl acetate-hexane; 2:3) to yield 0.3 g of 4-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:28]([Cl:29])=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.O.C[C:32]([N:34](C)C)=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:29][C:28]1[C:2]([C:32]#[N:34])=[CH:3][C:4]2[N:8]=[CH:7][N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[O:16][C:12]=4[CH:11]=3)[C:5]=2[CH:27]=1
Reactant: CC(=O)N(C)C
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)oc4c3)c2cc1Cl
Temperature: 100 °C
Reaction time: 16 h
Yield: 13.5 %

Procedure:
A mixture of (1R,2R)-2-((6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (215 mg, 0.45 mmol), Zn(CN)2 (327 mg, 2.71 mmol), Pd2(dba)3 (82 mg, 0.09 mmol) and dppf (100 mg, 0.18 mmol) in DMA (10 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature, poured into water (20 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-chloro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile as a white solid (25 mg, 13.5%). 1H NMR (300 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 5.53 (s, 2H), 4.68 (d, J=4.5 Hz, 1H), 3.38-3.31 (m, 2H), 1.92-1.86 (m, 2H), 1.65-1.60 (m, 2H), 1.27-1.19 (m, 4H). LCMS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[O:8][CH3:9])[CH2:3][OH:4].[N:17]#[C:18]Br>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]([O:8][CH3:9])[CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:18]([NH2:17])=[N:1]2)=[CH:11][CH:12]=1
Reactant: N#CBr
Reactant: COC(CC[C@H](N)CO)c1ccc(Cl)cc1
Product: COC(CC[C@H]1COC(N)=N1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1d (S)-2-amino-5-(4-chloro-phenyl)-5-methoxy-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-[3-(4-chloro-phenyl)-3-methoxy-propyl]-4,5-dihydro-oxazol-2-ylamine (mixture of epimers). White solid. MS (ISP): 271.2 ([{37Cl}M+H]+), 269.2 ([{35Cl}M+H]+).