Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl benzylsulfide. The title compound was obtained in 74% yield following oxidation. 1HNMR (CDC13) δ 4.55 (2H, s), 6.66 (1H, d, JH,H=12.12), 7.16-7.65 (9H aromatic+1H ethylenic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]([C:20](=O)[CH:21]([CH3:23])[CH3:22])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][C@H:35]1[O:40][C:39]([CH3:42])([CH3:41])[O:38][C@@H:37]([CH2:43][C:44]([N:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:45])[CH2:36]1.CCCCCCC.C(O)(=O)C(C)(C)C>C1(C)C=CC=CC=1.O1CCCC1>[C:53]1([N:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](=[O:45])[CH2:43][C@@H:37]2[O:38][C:39]([CH3:42])([CH3:41])[O:40][C@H:35]([CH2:34][CH2:33][N:32]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:9]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:12])=[C:20]3[CH:21]([CH3:23])[CH3:22])[CH2:36]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Agent: CC(C)(C)C(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)OC(C)(C)O1
Temperature: 25 °C

Procedure:
A nitrogen purged 500 mL three-neck flask is charged with 4-fluoro-α-(2-methyl-1-oxopropyl)-γ-oxo-N,β-diphenylbenzenebutanamide (Baumann, supra) (13.6 g, 0.032 mol), (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide (10.0 g, 0. 027 mol), heptane (100 mL), pivalic acid (3 g), tetrahydrofuran (50 mL), and toluene (60 mL). The mixture is heated to reflux for 48 hours, cooled to room temperature, and diluted with toluene (300 mL). The solution is washed with 0.5N aqueous sodium hydroxide (150 mL), followed by 0.5N aqueous hydrochloric acid (250 mL), and concentrated by vacuum distillation to a foam. The product, (4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methyl ethyl)-N,4-diphenyl-1H-pyrrole-3 -carboxamide, is used in the next step without further purification. Fourier Transform Infrared Spectroscopy (FTIR) (KBr) 3450, 2860, 1650, 1620 cm-1 ;
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:27])[CH2:15][NH2:16])[CH2:12][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NC1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)NC1CCN(C(=O)CN)CC1
Reaction time: 12 h

Procedure:
A suspension of 287 mg [1-(2-Benzyloxycarbonylamino-acetyl)-piperidin-4-yl]-carbamic acid butyl ester and 0.1 g Pd/C (10%) in 25 ml ethanol was stirred under an atmosphere of hydrogen (3 bar) for 12 h. The mixture was filtrated over a plug of Celite, washed with ethanol and the combined wash solutions concentrated to give the title compound as colourless oil. Yield: 156 mg.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]([CH3:42])[CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:39](=[O:40])[CH2:38][N:37]([CH3:42])[C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.054 g, 0.00014 mol), 2-[(tert-butoxycarbonyl)(methyl)amino]acetic acid (0.0033 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-oxoethyl)-N-methylcarbamate. The solid was dissolved in dichloromethane (2 mL) and 25% trifluoroaceticacid in dichloromethane (4 mL) was slowly added into the reaction at 0° C. The reaction mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure. To the residue a 5 N aqueous solution of sodium hydroxide was addded to pH 11 at 0° C. The water phase was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(methylamino)-1-ethanone acetate (0.010 g, 0.00002 mol).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[NH:17][C:16]3[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=3[CH:10]=2)O1.Br[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([N:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32])[N:27]=[CH:26]2>>[C:33]([N:31]([CH3:32])[C:28]1[N:27]=[CH:26][C:25]2[C:30](=[C:21]([C:9]3[NH:17][C:16]4[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=4[CH:10]=3)[CH:22]=[CH:23][CH:24]=2)[N:29]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CN(c1ncc2cccc(Br)c2n1)C(C)(C)C
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Product: CN(c1ncc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1)C(C)(C)C
Yield: 22.9 %

Procedure:
2-(2-(tert-butyl(methyl)amino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (8 mg, 22% yield) as a yellow crystalline solid was prepared according to the procedure described for Example 370, using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (146 mg, 0.56 mmol), and 8-bromo-N-(tert-butyl)-N-methylquinazolin-2-amine (377a) (30 mg, 0.10 mmol) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 12.87 (1H, br. s.), 9.04 (1H, s), 8.07 (1H, dd, J=7.5, 1.3 Hz), 7.52 (1H, dd, J=7.8, 1.2 Hz), 7.23-7.30 (1H, m), 7.11 (1H, d, J=2.0 Hz), 5.40 (1H, br. s.), 3.66 (2H, td, J=6.8, 2.5 Hz), 3.37 (3H, s), 2.98 (2H, t, J=6.8 Hz), 1.67 (9H, s). m/z (ESI, +ve ion) 350.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>CN(C)C=O>[CH3:3][N:2]([CH3:1])[CH:4]=[CH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
DMF-DMA (45.4 g; 2.3 equiv.) was added under a nitrogen atmosphere to a solution of 4-methyl-3-nitrobenzoic acid (30 g; 1 equiv.) in dimethylformamide (150 ml). The resulting reaction mixture was heated for 17 h at 140° C. When the conversion was complete, the DMF was distilled off; 150 ml of methanol were added to the residue, and the mixture was stirred for 2 hours at room temperature and then crystallised overnight at 0-4° C. The resulting solid was filtered out and washed with ice-cold methanol and then with hexane. Drying yielded 4-(2-(dimethylamino)vinyl)-3-nitrobenzoic acid (28 g; 71.79%) in the form of a red solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:14][CH2:13][CH:12]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[N:11]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])C)=[O:28])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[OH:8][CH2:9][C:10]12[N:11]([C:27]([O:29][CH:30]([CH3:32])[CH3:33])=[O:28])[CH:12]([CH2:13][CH2:14]1)[CH2:15][O:35][CH2:34]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)N2C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1C2CCC1(CO)COC2
Temperature: 50 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A mixture of tert-butyl 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(p-tolylsulfonyloxymethyl)pyrrolidine-1-carboxylate (410 mg, 0.64 mmol) and TBAF (1 M in THF, 4 mL) in THF (2 mL) was stirred at 50° C. for 16 h. Then the mixture was diluted with ethyl acetate (50 mL) and washed with saturated NH4Cl (50 mL) three times and water (50 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford isopropyl 5-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 81j (73 mg, 47%) which was used for next step without further purification. MS: calc'd (MH+) 244, measured (MH+) 244.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][CH:22]([F:34])[O:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][N:18]([S:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH:22]([F:21])[F:34])[CH:25]=4)(=[O:32])=[O:31])[C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(c2cnc3[nH]ccc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(c2cnc3c(ccn3S(=O)(=O)c3cccc(OC(F)F)c3)c2)C1

Procedure:
This compound was prepared from 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-azetidine-1-carboxylic acid tert-butyl ester and 3-Difluoromethoxy-benzenesulfonyl chloride by the method outlined under Example 46.b.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([N:15]2[CH2:19][CH2:18][S:17][C:16]2=[S:20])=[O:14])=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:21]([N:23]1CCS[C:24]1=S)=[O:22].CN.C(O)(C)C.CO>ClCCl>[CH3:1][O:2][C:3]1[C:12]([C:13]([N:15]2[CH2:19][CH2:18][S:17][C:16]2=[S:20])=[O:14])=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1cc(C(=O)N2CCSC2=S)c(OC)c(C(=O)N2CCSC2=S)c1
Agent: CN
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CO
Product: CNC(=O)c1cc(C(=O)NC)c(OC)c(C(=O)N2CCSC2=S)c1

Procedure:
To a solution of compound 6A in dichloromethane, a mixture of 1 mL methylamine solution (40% wt in water, d=0.902) and isopropanol (10 mL) was added dropwise over 48 h. The reaction mixture was applied directly onto a gradient flash silica column (1-5% methanol in dicholoromethane). The desired product was obtained as a thick, yellow oil. Yield 2.9 g (68% based on methylamine).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:20]([C:22]4[C:27]([CH3:28])=[CH:26][C:25](/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32])=[CH:24][C:23]=4[CH3:35])[NH:19][C:18]=3[CH:36]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>O.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:20]([C:22]4[C:23]([CH3:35])=[CH:24][C:25](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:26][C:27]=4[CH3:28])[NH:19][C:18]=3[CH:36]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/c1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(/C=C/C(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl (E)-3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-acrylate (200 mg, 420 μmol), 1N NaOH (520 μL), and methanol (260 μL) was diluted with 3 mL of water/methanol (2:1) and stirred at ambient temperature for 18 h. The solution was then quenched with 1N HCl (520 μL), filtered, and the precipitate washed with water and dried, to yield (E)-3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-acrylic acid. 1H-NMR (DMSO-d6, 400 MHz): δ 8.31 (s, broad, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.67 (m, 1H), 7.58 (m, 3H), 7.37 (d, J=8.7 Hz, 2H), 6.63 (d, J=16.2 Hz, 1H), 2.15 (s, 6H), 1.29 (s, 9H). MS (ESI) m/z 468.2 (M+H): Retention time=1.24 min (Method 10).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([CH3:42])=[N:18][C:19]([CH3:41])=[C:20]([C:29](=[O:40])[NH:30]CCCC3C=CC=CC=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:44](F)(F)[C:45]([O-])=O>ClCCl>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:20]([CH2:23][CH2:22][CH2:27][C:45]3[CH:44]=[CH:20][CH:21]=[CH:16][CH:14]=3)([C:29]([NH2:30])=[O:40])[CH:19]([CH3:41])[N:18]=[C:17]([CH3:42])[C:16]=2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1
Reactant: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CC1=NC(C)C(CCCc2ccccc2)(C(N)=O)C(c2cccc(Cl)c2)=C1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
619 mg (1.05 mmol) of 4-[4-(3-chlorophenyl)-2,6-dimethyl-5-(3-phenylpropylcarbamoyl) pyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester was dissolved in 30 ml of dichloromethane. 15 ml of trifluoroacetate was added and stirred at room temperature for 2 hours. After concentration under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. By adding hexane to the residue, the solid substance was precipitated, filtered and dried under reduced pressure to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:31])=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:31])=[CH:26][CH:25]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 120 °C
Yield: 12 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.080 g, 0.24 mmol), tert-butyl 1-(4-aminophenyl)ethylcarbamate (0.067 g, 0.29 mmol), Xantphos (0.0057 g, 0.010 mmol) and Cs2CO3 (0.23 g, 0.71 mmol) in 1,4-dioxane (4 mL) was bubbled with nitrogen for 10 minutes. Palladium(II) acetate (0.0010 g, 0.0045 mmol) was added and the mixture was heated at 120° C. under microwave irradiation for 25 minutes. The mixture was partitioned between water and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to give the crude product. Purification by silica gel column chromatography (Combiflash Rf, 0-100% EtOAc in cyclohexane) gave the title compound 24 as a colourless oil (0.015 g, 12%). LCMS-C: rt 5.79 min; m/z 536 [M+H]+.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[OH:19][C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21]1>C(Cl)Cl>[C:1]([N:23]1[CH2:24][C@H:20]([OH:19])[CH2:21][C@H:22]1[C:25]([OH:27])=[O:26])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
The FMOC-trans-4-hydroxy-L-proline 57 was prepared as follows: 1.1 equivalents of FMOC-chloride is added to 1.0 equivalents of trans-4-hydroxy-L-proline (Aldrich company) and allowed to stir for 12 hour at 25° C. in 0.10M methylene chloride. The resulting mixture is quenched with water, washed with sodium bicarbonate and dried over magnesium sulfate (standard workup conditions). The crude compound can then be purified by flash chromatography. Mass Spectral analysis: m/e calc'd for C53H58O11N2Cs (M+Cs+): 1031.3095, found 1031.3143
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[C:27]1([CH3:28])[CH:29]=[CH:30][C:24]([S:21]([O:20][CH2:19][CH2:18][CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCO)CC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 0 °C
Yield: 57.8 %

Procedure:
To a chilled mixture of 3-(1-benzyloxycarbonyl-4-piperidyl)propanol (110 g) and pyridine (500 ml) is added portionwise tosyl chloride (100 g) for 2 hours with stirring. After stirring for further 1 hour, ice water (1 l) is added dropwise to the mixture. The resulting mixture is acidified by dropwise addition of concentrated hydrochloric acid at ice-bath temperature and extracted with ethyl acetate (1 l). The extract is washed successively with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is crystallized from ethanol to give 3-(1-benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (99 g) as a colorless crystals, mp 59°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1N)=[O:4].N([O-])=O.[Na+].[ClH:16]>O.[Cu]Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Cl:16])=[O:4]
Reactant: COC(=O)c1sc(C)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 3-Amino-5-methyl-thiophene-2-carboxylic acid methyl ester (5.0 g, 29.2 mmol) in 6N HCl (25 ml) was cooled to 0° C. (ice bath). A solution of sodium nitrite (2.01 g, 29.2 mmol) in water (5 ml) was added dropwise and the mixture was stirred at 0° C. for 60 min This mixture was then added to a solution of copper(I)chloride (2.89 g, 29.2 mmol) in conc. HCl (25 ml) at 0° C. The reaction mixture was stirred at room temperature then warmed to 65° C. until gas evolution had ceased. The reaction mixture was diluted with water and extracted with EtOAc (2×150 mL), washed with water, brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 4.4 g (79%) yellow oil product.
Reaction SMILES: NCCCCCCN.[CH2:9]([P:11]([CH2:18][CH2:19][CH:20]=[O:21])(=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10].[H][H]>[Ni].[OH-].[K+].O>[CH2:9]([P:11]([CH2:18][CH2:19][CH2:20][OH:21])(=[O:17])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10]
Reactant: [H][H]
Reactant: CCCCOP(=O)(CC)CCC=O
Agent: [Ni]
Agent: NCCCCCCN
Agent: [K+]
Solvent: O
Product: CCCCOP(=O)(CC)CCCO
Yield: 82.9 %

Procedure:
In a glass autoclave, 240 g of hexamethylenediamine, 52 g of water, 6.4 g of Raney® nickel (doped with 1.5% by weight of chromium), 0.18 g (4 mmol) of potassium hydroxide, 75.1 g (0.37 mol) of butyl ethyl(2-formylethyl)phosphinate (produced in as Example 9) are reacted at 50° C. with hydrogen at 25 bar. Following a reaction time of 8 hours, the autoclave was let down. For purification, the reaction solution is filtered, passed through a column charged with Deloxan® THP II and concentrated in vacuo. The product is purified by chromatography to obtain 63.9 g (83% of theory) of butyl ethyl(3-hydroxypropyl)phosphinate as colorless oil.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Cl.[I-].[K+]>>[ClH:32].[ClH:1].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:28]1[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C:22]([C:20]2[CH:19]=[CH:18][C:14]3[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][C:7]4[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=4)[CH2:12][C:13]=3[CH:21]=2)=[O:31])[CH2:30][CH2:29]1
Reactant: ClCc1ccccc1Cl
Reactant: O=C(CCC1CCNCC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: O=C(CCC1CCN(Cc2ccccc2Cl)CC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2

Procedure:
Using 1-[2-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-(4-piperidinyl)-1-propanone(free base) obtained in Example 211, 2-chlorobenzylchloride, and potassium iodide, the procedure of Example 51-3 was otherewise repeated to provide the title compound as colorless amorphous powders.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:19])[CH3:18])[C:12]=1[OH:20]>CO>[OH:20][C:12]1[C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]([OH:19])[CH3:18]
Reactant: CC(=O)c1cccc(Sc2ccccc2F)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(Sc2ccccc2F)c1O
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
Sodium borohydride (320 mg) was added to a solution of 2-(2-fluorophenylthio)-6-acetylphenol (2.2 g) in methanol (50 ml) in 5 minutes at 10° C., and stirred at 10° C. for 10 minutes and at room temperature for 10 minutes. The reaction mixture was evaporated under reduced pressure. To the residue was added 10% hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily 1-[2-hydroxy-3-(2-fluorophenylthio)phenyl]ethanol (2.1 g).