Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[CH3:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([CH3:33])=[O:32])[CH:27]=[CH:26][C:25]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:31](=[O:32])[CH3:33])=[CH:29][C:24]=2[CH3:23])=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: CC(=O)Nc1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c(C)c1
Temperature: 90 °C
Yield: 20.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 4-bromo-3-methylacetanilide (0.228 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.020 g) in ethanol (3 ml) with heating at 90° C. for 2 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane, then by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution to give the title compound as an oil (0.041 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:25][C:26]2[CH:27]=[C:28]([N:32](C)[C:33](=O)OC(C)(C)C)[CH:29]=[CH:30][CH:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18]COCCOC)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(Cl)Cl.CO>FC(F)(F)C(O)=O>[F:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COCCOCOCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N(C)C(=O)OC(C)(C)C)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CNc1cccc(Nc2nc(Nc3ccc(OCCO)cc3)ncc2F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
In a 25 mL, 3-neck RBF equipped with a calcium chloride guard tube, tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamate (0.4 g) in was charged in trifluoroacetic acid (6.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 8 hr. The reaction was monitored by TLC using DCM: methanol (9.6:0.4) as mobile phase. After completion of the reaction, the reaction mixture was quenched in water and neutralized with sodium bicarbonate. Product was extracted in DCM and the organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Crude material was purified by using Combiflash chromatography. Product was eluted with 1.7% methanol in DCM and concentrated to give 0.105 g of 2-(4-((5-fluoro-4-((3-(methylamino)phenyl)amino)pyrimidin-2-yl)amino)phenoxy)ethanol. M+1=457.8. 1H NMR: DMSO-d6 (400 MHz): 2.65 (d, 3H, J=5.2), 3.69 (t, 2H, J=4.8), 3.92 (t, 2H, J=4.8), 4.85 (t, 1H, J=5.6), 5.54 (d, 1H, J=4.8), 6.29 (s, 1H), 6.79 (d, 2H, J=8.8), 6.86 (s, 1H), 7.03 (s, 2H), 7.55 (d, 2H, J=9.2), 8.02 (s, 1H), 8.93 (s, 1H), 9.04 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:13])=[CH:7][C:3]=1[C:4](O)=[O:5].CCO.O>C1COCC1>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:13])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1cc(Br)cc(C(=O)O)c1N
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(Br)cc(CO)c1N
Temperature: 0 °C
Reaction time: 120 h

Procedure:
2-amino-5-bromo-3-methoxybenzoic acid (20.0 g, 81.30 mmol) is suspended in 250 mL THF, cooled to 0° C. and combined with borane-THF complex (315 mL, 0.315 mol). The reaction mixture is stirred for 5 d at 20° C. and then combined with 10 mL EtOH, stirred for 15 min and then stirred into 250 mL water. The mixture is extracted 3× with DCM, the combined organic phases are dried and the solvent is eliminated in vacuo. The crude product is suspended in DCM and extracted 2× with 400 mL 1 N hydrochloric acid. The combined aqueous phases are adjusted to pH 5-6 with potassium carbonate, the precipitate formed is filtered off and (2-amino-5-bromo-3-methoxy-phenyl)-methanol (HPLC-MS: tRet.=1.41 min, MS(M+H)+=232/234; method FEC3) is obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH:8]2[CH2:12][CH:11]([CH2:13][O:14]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:10]=[CH:9]2)[CH:6]=[CH:5][N:4]=[C:3]1[C:34]([O:36][CH3:37])=[O:35]>C(O)(=O)C.O>[OH:14][CH2:13][CH:11]1[CH2:12][CH:8]([N:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:34]([O:36][CH3:37])=[O:35])[C:2]2=[O:1])[CH:9]=[CH:10]1
Reactant: COC(=O)c1nccn(C2C=CC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nccn(C2C=CC(CO)C2)c1=O
Temperature: 80 °C
Yield: 75.8 %

Procedure:
In 2.0 mL of 80% aqueous solution of acetic acid was dissolved 0.20 g of methyl 3-oxo-4-{4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-3,4-dihydro-2-pyrazinecarboxylate, and the solution thus obtained was heated at 80° C. for one hour. The reaction mixture was allowed to cool and diluted with 10 mL of water, the deposited precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [eluent: ethyl acetate] to obtain 77 mg of methyl 4-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate as a light yellow oily product.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Br:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 95 %

Procedure:
In a manner similar to the method described in Example 1d, rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 63b (2 g, 3.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.1 g, 95%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH2:14][F:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]1[C@@H:13]([CH2:14][F:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of (3S,4S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (Pk1) (1.012 g, 2.87 mmol) in CH2Cl2 (10 mL) at 0° C. was added TFA (2.212 mL, 28.7 mmol) and the resulting mixture was allowed to warm to rt and stir for 1 hr. The reaction mixture was concentrated and redissolved in 70 mL of CH2Cl2 and was washed with 20 mL of 2M Na2CO3 solution and 20 mL of brine then dried over Na2SO4. Filtration and concentration afforded the title compound (0.718 g, 99% yield). 1H NMR (500 MHz, chloroform-d) δ 7.41-7.31 (m, 5H), 5.24-5.08 (m, 2H), 4.77-4.43 (m, 2H), 3.75-3.57 (m, 3H), 3.37 (s, 2H), 2.66-2.49 (m, 1H). MS(ES+) m/z: 253.2 (M+H); HPLC retention time: 1.023 min (analytical HPLC Method B). Chiral purity: 99.9% ee (chiral HPLC conditions: column: CHIRALPAK® AD-H (25×0.46 cm, 5 μm), 35% MeOH in CO2, 3 mL/min, 45° C., 220 nm, 100 bar).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]([CH3:24])[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[S:17])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(C)=O>[CH2:38]([O:37][C:35]([C:34]1[S:17][C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:15]([CH3:24])[C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([S:5](=[O:7])(=[O:6])[N:4]=[CH:3][N:2]([CH3:26])[CH3:1])=[CH:9][CH:10]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CI
Reactant: CC(C(=O)c1ccc(S(=O)(=O)N=CN(C)C)cc1)C(=S)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a stirred solution of N,N-dimethyl-N′-((4-(2-methyl-3-morpholino-3-thioxopropanoyl)phenyl)sulfonyl)formimidamide (compound 24c, 0.180 g, 0.45 mmol) in dry acetone (15 ml) was added potassium carbonate (0.45 g, 3.17 mmol) at room temperature. The resulting mixture was stirred at 55-60° C. for 2 hr. The reaction mixture was cooled to 0° C. and to this was added ethyl iodoacetate (0.097 g, 0.053 ml, 0.45 mmol) in a dropwise manner. The reaction mixture was stirred at reflux temperature for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was allowed to warm to room temperature and filtered through a celite pad. The celite pad was washed with acetone (2×10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 50-55% ethyl acetate in hexanes as an eluent to obtain the title compound (0.091 g, 43%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](C4C=CC=C(B5OC(C)(C)C(C)(C)O5)C=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH2:42]([O:49][C:50]1[C:51]([C:57]2[C:65]([CH2:66][OH:67])=[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][N:59]3[N:58]=2)=[N:52][C:53](Cl)=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[CH2:42]([O:49][C:50]1[CH:55]=[CH:54][C:53]([C:18]2[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=3[CH:17]=2)=[N:52][C:51]=1[C:57]1[C:65]([CH2:66][OH:67])=[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][N:59]2[N:58]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: OCc1c(-c2nc(Cl)ccc2OCc2ccccc2)nn2ccccc12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(-c4nn5ccccc5c4CO)n3)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzofuran-3-carboxamide (452 mg, 0.90 mmol) and compound (2-(3-(benzyloxy)-6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanol (300 mg, 0.82 mmol) in dioxane/H2O (5 mL/1 mL) was added Pd2(dba)3 (90 mg, 0.1 mmol), X-Phos (95 mg, 0.2 mmol) and K3PO4 (1.2 g, 2.4 mmol) under N2. After stirred at 100° C. overnight, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (petroleum ether:ethyl acetate=1:2) to provide the product of compound 5-(5-(benzyloxy)-6-(3-(hydroxymethyl)pyrazolo[1,5-a]pyridin-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, yield: 53%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.47 (d, J=8.8 Hz, 1H), 8.00 (dd, J=5.2, 8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.30˜7.24 (m, 7H), 7.16˜7.11 (m, 1H), 7.13 (dt, J=0.8, 6.8 Hz, 1H), 5.22 (s, 2H), 4.74 (s, 2H), 3.29 (s, 3H), 2.93 (s, 3H), 2.89 (s, 3H). MS (M+H)+: 706.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH2:29]O)[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:55]I>C1COCC1.CCOC(C)=O>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH2:29][I:55])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(-c2ccc3cc(CO)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3cc(CI)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 44.9 %

Procedure:
To a solution of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyl alcohol (0.365 g, 0.92 mmol), triphenylphosphine (0.366 g, 1.39 mmol) and imidazole (0.095 g, 1.39 mmol) in 7 mL of anhydrous THF at 0° C. was added dropwise a solution of I2 (0.303 g, 1.19 mmol) in 4 mL of anhydrous THF. After 30 minutes the mixture was diluted with EtOAc and washed with sodium thiosulfate aq. (100 mL), brine (100 mL), dried with magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc 100 to 95:5) to give 0.210 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyliodide (45%). 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.18 (m, 9H), 3.89 (s, 3H), 4.65 (s, 2H), 6.98 (d, J=8.7 Hz, 1H), 7.46–7.57 (m, 3H), 7.71–7.93(m, 5H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@H:47]([CH2:64][C:65]3[CH:70]=[C:69]([C:71]([F:74])([F:73])[F:72])[C:68]([NH2:75])=[C:67]([Cl:76])[CH:66]=3)[C:48]([N:50]3[CH2:55][CH2:54][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][C@@H:57]4[C:61]([OH:63])=[O:62])[CH2:52][CH2:51]3)=[O:49])=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:77]=[CH:78][CH:79]=[CH:80][C:33]=2[NH:32]1.O[CH2:82][C:83]([N:85]([CH3:87])[CH3:86])=[O:84]>CN(C=O)C>[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@H:47]([CH2:64][C:65]3[CH:70]=[C:69]([C:71]([F:72])([F:74])[F:73])[C:68]([NH2:75])=[C:67]([Cl:76])[CH:66]=3)[C:48]([N:50]3[CH2:51][CH2:52][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][C@@H:57]4[C:61]([O:63][CH2:82][C:83](=[O:84])[N:85]([CH3:87])[CH3:86])=[O:62])[CH2:54][CH2:55]3)=[O:49])=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:77]=[CH:78][CH:79]=[CH:80][C:33]=2[NH:32]1
Reactant: CN(C)C(=O)CO
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)O)CC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)[C@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
25 mg (0.08 mmol) TBTU and 11 μL (0.08 mmol) triethylamine were added to a solution of 50 mg (0.07 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl)-piperid in-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF and stirred for 10 min at RT. 8.1 mg (0.08 mmol) 2-hydroxy-N,N-dimethyl -acetamide were added to the reaction mixture and this was shaken overnight at RT. After filtration through a syringe filter the reaction solution was purified by HPLC without further working up. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:15])[CH2:10][C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]([CH3:15])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H](CC=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a 50 ml round bottom flask was introduced 200 mg (0.86 mmol) of methyl (S)-3-t-butyldimethylsilyloxybutanoate, to which was added 2.5 ml dry CH2Cl2. The reaction was stirred in a dry ice/acetone bath, and 1.72 ml (2 eq.) of 1M diisobutylaluminum hydride in toluene was added dropwise. After stirring for 1 hour at -78° C., the reaction was quenched with 2 ml of MeOH and warmed to room temperature. The reaction was diluted with 25 ml of CH2Cl2 and 8 ml saturated aq. potassium sodium tartrate was added. The organic layer was separated and dried over MgSO4 and the solvent was removed under reduced pressure. Thin layer chromatography using 10% ethyl acetate in hexane showed complete and clean conversion to a lower Rf spot. This afforded 170 mg (98%) of the product, (S)-3-t-butyldimethylsilyloxybutanal, which was used without purification to avoid racemization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[I:22]I>>[I:22][C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S(=O)(Nc1cc(Br)c(O)c2ccccc12)c1cccs1
Reactant: II
Product: O=S(=O)(Nc1cc(I)c(O)c2ccccc12)c1cccs1
Yield: 100 %

Procedure:
was prepared according to the procedure for 4b except using I2 solid. The reaction afforded title compound 129.4 mg (100%) as a brown solid, m.p.: 134-136° C.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:1])[C:3]([NH:29][CH:27]([CH3:28])[CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:5]
Reactant: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O
Reactant: Cc1ccc(CC(c2ccccc2)C(C)N)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CC(c2ccccc2)C(C)NC(=O)C(C)(C)Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (Reference example 55, 250 mg, 1.04 mmol) and 4-(4-methylphenyl)-3-phenylbutan-2-amine (Reference example 102, 260 mg, 1.04 mmol, mixture of 4 isomers) in CH2Cl2 (5.5 mL) at RT was added diisopropylethylamine 272 μl, 1.56 mmol) followed by PyBOP (649 mg, 1.25 mmol) and the reaction mixture stirred overnight. The reaction was purified by loading the reaction mixture directly onto a silica gel column and eluting from 0-30% EtOAc/hexane to give the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a ZORBAX RxSi column eluting 97% hexane: 3% ethanol at 20 mL/min with retention times of:
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C@@H:5]([CH2:15][OH:16])[O:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH2:15][C@H:5]1[O:4][CH2:3][C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6]1)(=[O:27])=[O:26]
Reactant: C[C@@H]1CO[C@H](CO)CN1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.3 %

Procedure:
To a solution of [(2S,5R)-5-methyl-4-(phenylmethyl)-2-morpholinyl]methanol (5 g, 22.59 mmol) and triethylamine (9.45 mL, 67.8 mmol) in CH2Cl2 (50 mL) stirred under nitrogen at 0° C. was added a solution of methanesulfonyl chloride (4.37 mL, 56.5 mmol) in CH2Cl2 (15 mL) dropwise during 5 minutes. The reaction mixture was stirred at 25° C. for 2.5 hours. Then the reaction mixture was washed with saturated NaHCO3 aqueous solution (2×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (8.0 g) as a yellow oil. LC-MS (ES) m/z=300 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11].C1COCC1.[CH3:17][C:18]1[C:19]([N:23]=[C:24]=[S:25])=[CH:20][S:21][CH:22]=1>C(N(CC)CC)C>[NH2:3][C:4]1[C:8]([NH:9][C:24]([NH:23][C:19]2[C:18]([CH3:17])=[CH:22][S:21][CH:20]=2)=[S:25])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11]
Reactant: Cc1cscc1N=C=S
Reactant: Cc1sc(C)c(N)c1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1c(C)sc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 g of 3,4-diamino-2,5-dimethylthiophene dihydrochloride, 60 ml of anhydrous THF and 1.05 g of triethylamine was stirred at room temperature for 30 minutes and then admixed with 0.902 g of 4-methyl-3-thienyl isothiocyanate. After the mixture had been heated to 35–40° C. for 15 minutes, it was stirred for approx. 18 hours, the solvent was distilled off and the residue was admixed with water and extracted repeatedly with ethyl acetate. After the solvent of the combined organic phases had been distilled off, the residue was purified by column chromatography on silica gel using a solvent mixture of equal parts of toluene and ethyl acetate. After the solvent had been distilled off under reduced pressure, a semicrystalline oil was obtained and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH2:15][CH2:14]1>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH2:15][CH2:14]1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: Clc1ccccc1OCC1CO1
Solvent: CCO
Product: O=C1NCCCN1C1CCN(CC(O)COc2ccccc2Cl)CC1

Procedure:
A solution of 9.2 g of 1-(o-chloro-phenoxy)-2,3-epoxypropane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from chloroform/petroleum ether to yield the 1-[3-(o-chloro-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 150°-153° C.