Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.FC(F)(F)S(O[Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])(=O)=O>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([O:14][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[CH:4]=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:8]=1
Reactant: OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To a stirred solution of (2R)-bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol ((R)-33, 1.051 g, 2.0 mmol) and triethylamine (TEA, 1.68 mL, 12.0 mmol, 6.0 equiv) in anhydrous methylene chloride (5.0 mL, 78 mmol) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf, 1.41 mL, 6.0 mmol, 3.0 equiv). The resulting reaction mixture was stirred at room temperature for 20 h before being heated at 100° C. for 10-20 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-10% EtOAc/hexane gradient elution to give (2R)-2-(bis[3,5-bis(trifluoromethyl)phenyl][tert-butyl(dimethyl)silyl]oxymethyl)pyrrolidine ((R)-36, 1.167 g, 1.279 g theoretical, 91.2% yield) as a very viscous colorless syrup. For (R)-36: 1H NMR (CDCl3, 400 MHz) δ ppm 8.09 (s, 2H), 7.87 (s, 2H), 7.75 (s, 2H), 4.33 (m, 1H), 2.98 (m, 1H), 2.54 (m, 1H), 1.86 (m, 1H), 1.70 (m, 1H), 1.56 (m, 2H), 0.95 (s, 9H), −0.21 (s, 3H), −0.45 (s, 3H); C27H29F12NOSi (MW, 639.59), LCMS (D) m/e 640.4 (M++H).
Reaction SMILES: C1(C[NH:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>[Pd].C(O)C>[NH2:8][CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C1CC2(CCC1NCc1ccccc1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC2(CCC1N)OCCO2
Reaction time: 6 h
Yield: 93.2 %

Procedure:
Ethyl 8-[(phenylmethyl)amino]-1,4-dioxaspiro[4.5]-decane-7-carboxylate (397.2 g, 1.3 mole) was combined with 2563 ml of ethanol and 80 g of 5% palladium on activated carbon and hydrogenated at 50 p.s.i. for 6 hours at 45°-50° C. The catalyst was separated by filtration, and the filtrate was evaporated. When taken up in methylene chloride a semi-solid precipitated and was filtered out. The filtratew was evaporated to yield 277.7 g (97.4%) of the title product.
Reaction SMILES: CC#N.[OH2:4].[C:5]1(/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl>CC#N>[C:5]1([C@H:11]2[C@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:4]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O
Reactant: C(=C/c1ccccc1)\c1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: c1ccc([C@@H]2O[C@H]2c2ccccc2)cc1
Yield: 99 %

Procedure:
Under a flow of F2 (10% in N2) of 20.0 ml min−1 (3.33 mmol h−1) passed through first conduit 12, MeCN:H2O (4:1, 4.95 ml) was added to conduit 16 at a rate of 9.90 ml h−1 (110.0 mmol h−1) and trans-stilbene 24 (0.36 g, 2.0 mmol) (in a 1:1 mixture of DCM:MeCN) was added to conduit 38 at a rate of 9.90 ml h−1. All reaction fluids were collected in a pot 22 containing sodium bicarbonate solution 25 (50 ml). The reaction mixture was then added to another 25 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield trans-2,3-diphenyloxirane (0.39 g, 1.99 mmol, 99%) as a yellow solid, with no purification required;
Reaction SMILES: C(O[C@H]1CC[C@@]2(C)[C@@H](CC=C3[C@@H]2CC[C@@]2(C)C3=CC[C@@H]2[C@H](C)CCCC(C)C)C1)(=O)C1C=CC=CC=1.[C:37]([O:45][C@H:46]1[CH2:70][CH2:69][C@@:68]2([CH3:71])[C@@H:48]([CH2:49][CH:50]=[C:51]3[C@@H:67]2[CH2:66][CH2:65][C@@:64]2([CH3:72])[C@@:52]43[O:73][C@H:53]4[CH2:54][C@@H:55]2[C@H:56]([CH3:63])[CH2:57][CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:47]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl(O)(=O)(=O)=O>CC(C)=O>[C:37]([O:45][C@H:46]1[CH2:70][CH2:69][C@@:68]2([CH3:71])[C@@H:48]([CH2:49][CH2:50][C:51]3[C@@H:67]2[CH2:66][CH2:65][C@@:64]2([CH3:72])[C:52]=3[C:53](=[O:73])[CH2:54][C@@H:55]2[C@H:56]([CH3:63])[CH2:57][CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:47]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Agent: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
In accordance with Scheme III, the epoxidation of (3β,5α)cholesta-7,14-dien-3-ol benzoate (2) to (3β,5α, 15α)-14,15-epoxycholest-7-en-3-ol benzoate (3) is carried out as described in Scheme II. Also when the epoxyolefin (3) is treated with a catalytic amount of a protic acid (preferably 70% perchloric acid) in acetone at a controlled temperature of about 23°-26° C. for 3 hours, the precursor compound (3β,5α)-3-(benzoyloxy)cholest-8(14)en-15-one (6) is obtained. However, it has been discovered that when the preceding reaction is conducted at a temperature of from about 15°-22° C. for 3 hours, the novel intermediate compound (3β,5α)-3-(benzoyloxy)cholest-7-en-15-one (5) is produced Further treatment of (5) with a protic acid (preferably 70% perchloric acid) in acetone at about 23°-26° C. for 2 hours also gives the precursor compound (6) which is refluxed with potassium carbonate in a protic solvent, preferably methanol, as described hereinbefore in Scheme II to give the product (7). The alternate debenzoylation procedures described in Scheme II may also be used to give the product (7).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[Br-].C([Zn+])C=C.C(Br)C=C.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)(=[O:17])[CH3:16].[Na+].[Br-].Cl>C1COCC1.[Zn].[Hg](I)I>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([C:15]([OH:17])([CH3:16])[CH2:2][C:3]([OH:5])=[O:4])=[CH:19][CH:20]=1
Reactant: O=C(O)CBr
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: C=CC[Zn+]
Agent: Cl
Agent: I[Hg]I
Solvent: C1CCOC1
Solvent: C=CCBr
Product: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 12.9 g. of bromoacetic acid in 50 ml. of THF is added slowly dropwise at 10°-15° to a solution of 19 g. of allyl-zinc bromide in 200 ml. of THF, prepared by reacting allyl bromide with zinc filings in THF. A solution of 23.2 g. of 4-acetyl-2',4'-difluorobiphenyl in 100 ml. of THF, 6.5 g. of zinc filings, 100 mg. of HgI2 and 10.3 g. of NaBr are added to the reaction mixture, which contains an intermediate of the formula BrCH2 -COOZnBr, and heated under reflux until all the zinc has dissolved. After the alcholate formed has been decomposed with dilute hydrochloric acid, the mixture is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid, m.p. 121°-123°.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17](O)=[O:18])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.Cl.[NH2:27][C@H:28]([C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1)[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:27][C@H:28]([C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)[CH3:29])=[O:18])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(-c5ccccc5)cc4)c23)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylic acid (0.20 g), methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride, and HATU was added DMF (4.0 mL), followed by adding diisopropylethylamine (0.26 mL) under ice-cooling and then stirring at room temperature for 22 hours. Again, the mixture was ice-cooled, a 10% aqueous citric acid solution (4.0 mL) was added thereto, and the precipitated solid was collected by filtration, washed with water, and dried at 60° C. under reduced pressure to obtain methyl 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (0.30 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[CH:7]=1.[H-].[Na+].CI.[C:20](=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([N:8]([CH:9]2[CH2:11][CH2:10]2)[CH3:20])[CH:7]=1
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cc(Cl)c(F)cc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
To a solution of 500 mg (2.17 mmol) (5-chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-amine (J. Med. Chem. 1992, 35(8), 1385) in 5 mL N,N-dimethylformamide was added 104 mg (2.385 mmol) sodium hydride (60% dispersion in mineral oil) and 339 mg (2.385 mmol) methyl iodide. The reaction mixture was stirred for 6 hours at room temperature and then poured on 30 mL 10% aqueous sodium bicarbonate solution and 30 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate 100:0 to 80:20) to give 433 mg (82%) of the desired compound as a yellow oil. MS (ESI): m/z=245.049 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=O)[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.B(F)(F)F.CCOCC.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CCN(CCCCl)CC2
Temperature: 100 °C

Procedure:
Here, 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane (1.5 g, 0.005 mol) is dissolved in tetrahydrofuran (20 ml) and, after the addition of boron trifluoride etherate (0.55 ml, 0.0044 mol) and a 2 molar solution of boranedimethylsulfide in toluene (3 ml, 0.006 mol), the mixture is refluxed for 2 hours. Then, further boranedimethylsulfide solution (3 ml) is added and again the mixture is refluxed for 2 hours. After decomposition with methanol the solvents are distilled off and the residue is heated to 100° C. for 10 minutes with semi-concentrated hydrochloric acid (6 ml). The reaction product is extracted with ethyl acetate, the acidic aqueous phase is made alkaline and again extracted with ethyl acetate. The extract is dried, concentrated by evaporation and purified over an aluminium oxide column (activity stage II-III) with methylene chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[N:20]1([C:17]2[CH:16]=[CH:15][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][CH:18]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3CCCC3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc(N2CCCC2)ccc1C1CCNCC1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of furnished 4-(4-Pyrrolidin-1-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in ethyl acetate (5 mL) was added 4 N hydrogen chloride in ethyl acetate (10 mL) at room temperature. After stirring for 3 h, solvent was removed in vacuo, and the resulting solid was purified by HPLC. Sodium hydroxide was added to the resulting fractions and the aqueous layer was extracted by dichloromethane. Organic layer was washed with brine, and passed through Cerite. Removal of the solvent under reduced pressure afforded 4-(4-pyrrolidin-1-yl-phenyl)-piperidine (1.01 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1Cl)=[O:4].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:4]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1ccc(N)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nnc(Cl)cc1Nc1ccc(C)cc1
Temperature: 110 °C
Yield: 79.8 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid methyl ester (200 mg, 0.966 mmol), p-toluidine (104 mg, 0.966 mmol) and N,N-diisopropylethylamine (0.34 mL, 1.93 mmol) were dissolved in N,N-dimethylacetamide (2.4 mL), then heated at 110° C. for 1 h. The reaction mixture was cooled, then poured into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and then the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica, 0 to 50% ethyl acetate in hexanes) gave 6-chloro-4-p-tolylamino-pyridazine-3-carboxylic acid methyl ester (214 mg, 79%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 9.61 (br. s., 1H) 7.23-7.32 (m, 2H) 7.13 (d, J=7.9 Hz, 2H) 6.96 (s, 1H) 4.08 (s, 3H) 2.41 (s, 3H); LCMS (EI/CI) m/z: 278 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH:19]3C[CH2:21][CH2:20]3)=[O:18])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.Cl.N[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O.ClC1N=C2C(N=CN2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(Cl)(=O)CCC>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:18])[CH2:19][CH2:20][CH3:21])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:3]=1
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Agent: CCCC(=O)Cl
Agent: Cl
Agent: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Product: CCCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared by the same method as cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide from (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) and butyryl chloride to afford the title compound (48 mg). LCMS (electrospray): m/z [MH+] 535.26. 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.30(m, 8H), 7.25-7.15(m, 2H), 4.75(m, 1H), 4.60(m, 1H), 4.50(m, 1H), 4.20(m, 2H), 3.95(m, 1H), 2.85(m, 1H), 2.35(m, 2H), 2.05(m, 1H), 1.70(m, 2H), 1.00(m, 3H)
Reaction SMILES: C([BH3-])#N.[Na+].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=O)[CH2:15]2)=[CH:6]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[OH-].[Na+]>CO.C(O)(=O)C.O>[N:24]1([C@@H:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:5][CH:6]=3)[CH2:15]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CC(c2c[nH]c3ccccc23)c2ccccc21
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: c1ccc2c(c1)[C@H](c1c[nH]c3ccccc13)C[C@@H]2N1CCCCC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Sodium cyanoborohydride (61 mg; 0.97 mmol ) was added to 3-(1H-indol-3-yl)-indan-1-one (200 mg; 0.81 mmol ) and piperidine (344 mg; 4.05 mmol ) in 3 mL methanol and 0.5 mL acetic acid. The reaction mixture was stirred 30 minutes at 150° C. under microwave irradiation using the Emry Optimizer™ instrument. The reaction mixture was poured into water and made basic with 27% aqueous NaOH. The mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated in vacuo. cis-3-(3-Piperidin-1-yl-indan-1-yl)-1H-indole was obtained after flash chromatography (ethyl acetate, heptane, triethylamine, silica gel).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Product: Cc1cccc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)n1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-(6-methyl-pyridin-2-yl)-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.51 (d, 1H), 7.83 (s, 1H), 7.68 (m, 2H), 7.34 (m, 1H), 7.27 (d, 1H), 7.16 (d, 1H), 6.97 (dd, 1H), 6.57 (d, 1H), 6.10 (s, 1H), 2.52 (s, 3H), 2.40 (s, 3H); RP18-HPLC RT: 5.70 minutes; API MS: 371 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C@@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]2[CH2:14][NH:15][CH2:16][CH2:17][CH:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@@H](C1)OCCN2Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCOC3CNCCC32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-tert-butyl 1-benzyloctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate (82 g, 246 mmol) in EtOAc (500 mL) at 0° C. was added HCl in EtOAc (1500 mL, 4 M) dropwise. The reaction was stirred at room temperature for 2 hours. The mixture was concentrated to afford 1-benzyloctahydro-1H-pyrido[3,4-b][1,4]oxazine as a mixture of trans diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(Cl)cc1[C@H](OCCO)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1[C@H](OCCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (7 g, 18.3 mmol) in dry CH2Cl2 (100 mL) was added Et3N (54 g, 10 mL, 0.73 mmol) at −5-0° C. Then a solution of MsCl (4.2 g, 36.5 mmol) in dry CH2Cl2 (50 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. The reaction mixture was washed with 10% citric acid solution (30 mL), NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (8.4 g), which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CCCCBr
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OCCCCC(=O)O)c(Cl)c1Cl
Temperature: 60 °C

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (7 g, 0.03 mole), potassium carbonate (7.5 g, 0.054 mole) and ethyl 5-bromovalerate (9.5 g, 0.045 mole) in N,N-dimethylformamide (60 ml) were stirred and heated at 60° C. for 3 hours. The mixture was treated with 10 normal sodium hydroxide (12 ml) and water (50 ml), then stirred and heated on a steam bath for 2.5 hours. The solution was poured into ice water containing hydrochloric acid. The solid that separated was removed by filtration, washed with water and dried. The product (9.8 g) was recrystallized from butyl chloride to give 5-(2,3-dichloro-4-butyrylphenoxy)valeric acid, m.p. 102°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH:15]([CH3:19])[NH:14]1>C(OCC)(=O)C>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:8]2[C:7]([F:11])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=2)[CH2:18]1
Reactant: CC1CNCC(C)N1
Reactant: O=Cc1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2cc(F)c(C=O)cc2F)C[C@H](C)N1
Reaction time: 8 h

Procedure:
To a solution of 2,4,5-trifluorobenzaldehyde (1 eq) in ethyl acetate at room temperature was added 2,6-dimehtylpiperazine (2 eq). After being stirred overnight, the solution was washed with water, aqueous sodium bicarbonate, brine and dried, and purified on silica gel to give 4-(cis-3,5-dimethylpiperazinyl)-2,5-difluorobenzaldehyde.