Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:20])=[C:6]([CH3:21])[C:5]=1[CH2:22][CH3:23])[CH:2]=C.NC(N)=S.C[OH:29]>C(Cl)Cl.N1C=CC=CC=1>[CH2:22]([C:5]1[C:6]([CH3:21])=[C:7]2[C:11]([C:10](=[O:20])[O:9][CH2:8]2)=[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:4]=1[CH2:1][CH:2]=[O:29])[CH3:23]
Reactant: C=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: CO
Agent: NC(N)=S
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of 6-allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (261 mg, 0.788 mmol) in MeOH (5 mL), CH2Cl2 (5 mL) and pyridine (50 μL) was cooled to −78° C. using a dry ice/acetone bath according to the procedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through the reaction via a gas dispersion tube until the reaction became blue in color (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for another 15 minutes, by which time the blue color had disappeared. To this solution at −78° C. was added thiourea (59.9 mg, 0.788 mmol) in one portion, and the cooling bath was removed. The reaction was allowed to warm to room temperature and stirred for 15 hours. The reaction mixture was filtered and then partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 one more time and the organic extracts were combined, washed with aqueous 1N HCl, saturated NaHCO3 and brine and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded the crude product, which was purified by silica gel chromatography to afford 181 mg (69%) of the product as a white solid. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.11 (t, J=7.5 Hz, 3H), 1.19 (m, 2H), 2.21 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.90 (s, 2H), 4.36 (m, 2H), 5.18 (s, 2H), 9.71 (s, 1H) ppm.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[CH:7]1[N:11]=[CH:10][N:9]([C:12](N2C=NC=C2)=[O:13])[CH:8]=1>O1CCCC1>[N:9]1([C:12]([O:6][C@@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[O:13])[CH:8]=[CH:7][N:11]=[CH:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O[C@@H]1CCOC1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCOC1)n1ccnc1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of (R)-tetrahydrofuran-3-ol (500 mg, 5.68 mmol, 1.00 equiv) and CDI (2 g, 12.33 mmol, 2.17 equiv) in tetrahydrofuran (50 mL) was stirred overnight under nitrogen at 60° C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in 30 mL of DCM and washed with 1×50 mL of H2O. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to yield 0.95 g (92%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([CH:3]([CH3:11])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[C-:2].C(N(CCCC)C1C=CC=CC=1)CCC>>[CH3:11][C:3]1[N:1]=[CH:2][O:5][C:4]=1[O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [C-]#[N+]C(C)C(=O)OCCCC
Agent: CCCCN(CCCC)c1ccccc1
Product: CCCCOc1ocnc1C
Yield: 98.7 %

Procedure:
Example 5 is repeated except that a mixture of 11.8% by weight of n-butyl α-isocyanopropionate and 88.2% by weight of N,N-dibutylaniline is added continuously via the inlet (A). 4-Methyl-5-n-butoxyoxazole is obtained in a yield of 98.7% via the top takeoff B and the amine via the sidestream takeoff D.
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:22])[NH:12]1.[C:23](Cl)(Cl)=[S:24]>ClCCl>[N:7]([CH2:8][CH2:9][CH2:10][CH:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:22])[NH:12]1)=[C:23]=[S:24]
Reactant: COC(=O)CN1C(=O)NC(CCCN)C1=O
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CN1C(=O)NC(CCCN=C=S)C1=O
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
100 ml of a saturated solution of sodium hydrogen carbonate are added to a suspension of 2.65 g (10 mmol) of (11.1) in 30 ml of dichloromethane. After stirring for 10 min while cooling with ice, 1.53 ml (20 mmol) of thiophosgene are added to the methylene chloride phase. The mixture is stirred for 10 min, while cooling with ice, the phases are separated and the water phase is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate. 2.04 g (75%) of (11.2) are obtained after filtering and removing the solvent in vacuo.
Reaction SMILES: [C:1]([C:3](=[C:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:4](O)=[O:5])#[N:2].C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl>[C:1]([C:3](=[C:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:4]([Cl:25])=[O:5])#[N:2]
Reactant: N#CC(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: N#CC(C(=O)Cl)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a suspension of 2-cyano-3,3-bis(4-fluorophenyl)-2-propenoic acid (4 g, 14 mmol) in 10 mL of dry methylene chloride at room temperature was added oxalyl chloride (6 mL, 69 mmol) in one single portion. The reaction was stirred and warmed slowly to reflux for 45 minutes. The pale homogeneous solution was evaporated under reduced pressure to remove volatile solvent, then excess oxalyl chloride was removed under vacuum (20 mm Hg) at ambient temperature for 2 hours and under high vacuum (0.1 mm Hg) for 16 hours to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Reactant: Cc1ccc(CCl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc(C)cn4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.0, 6.5 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl)-5-methylpyridine (1.36 g, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture allowed to cool, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.0 g, 76.9%) as an off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.4 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=415.2. HPLC: (97.5%, Condition-A).
Reaction SMILES: N[C@@H](C(O)=O)C(C)(C)C.[BH4-].[Na+].[CH3:12][C:13]1[CH:32]=[CH:31][C:16]2[NH:17][C:18](=[O:30])[C:19](=[O:29])[CH:20]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[S:21][C:15]=2[CH:14]=1.C(O)(=O)C.O1CCCC1>O1CCCC1>[OH:29][C@@H:19]1[C:18](=[O:30])[NH:17][C:16]2[CH:31]=[CH:32][C:13]([CH3:12])=[CH:14][C:15]=2[S:21][C@@H:20]1[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(C2Sc3cc(C)ccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc([C@H]2Sc3cc(C)ccc3NC(=O)[C@H]2O)cc1
Temperature: -15 °C
Reaction time: 0.42 h
Yield: 80.6 %

Procedure:
A mixture of D-tert-leucine (721 mg), sodium borohydride (189 mg) and tetrahydrofuran (50 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to -15° C., and thereto is added a solution of 8-methyl-2-(4-methylphenyl)-1,5-benzothiazepine-3,4(2H, 5H)-dione (991 mg) in tetrahydrofuran (3 ml). Each 0.38 ml of 25% acetic acid/tetrahydrofuran solution (1.67 mmole as acetic acid) is added thereto at 25 minutes, and 2 hours 10 minutes after the beginning of the reaction, and the reaction solution is stirred at the same temperature for 20 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added 1N hydrochloric acid (70 ml). The precipitated crystal is collected by filtration, washed with water, and dried. The collected crystal is suspended in isopropyl alcohol (12 ml), and the mixture is heated with stirring at 80° C. for three hours. The mixture is cooled to 5° C., and allowed to stand for five hours. The precipitated crystal is collected by filtration, washed with cold isopropyl alcohol, and dried to give (2R,3R)-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (804 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][C@H:38]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:39][OH:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][C@@H:38]([CH2:39][OH:40])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Product: CC(C)C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-4-methyl-1-pentanol using methods similar to Example 563 to provide a pink solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (dd, J=6.42, 1.79 Hz, 6 H), 1.39-1.49 (m, 2 H), 1.55 (d, J=5.48 Hz, 4 H), 1.59-1.75 (m, 5 H), 2.35-2.45 (m, 2 H), 3.37 (d, J=8.00 Hz, 2 H), 3.40 (s, 2 H), 3.48 (s, 2 H), 4.04-4.13 (m, 1 H), 4.19 (s, 4 H), 4.93 (s, 1 H), 7.11-7.18 (m, 2 H), 7.41 (dd, J=8.74, 5.58 Hz, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.31 (d, J=8.63 Hz, 1 H), 17.26 (s, 1 H); ES+ MS: 567 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][CH:29]2[CH:34]3[CH2:35][CH:31]([CH:32]=[CH:33]3)[CH:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COCCN(C)C1CCc2ccc(N)c(OC)c2CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COCCN(C)C1CCc2ccc(Nc3ncc(Cl)c(NC4C5C=CC(C5)C4C(N)=O)n3)c(OC)c2CC1
Yield: 41 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-Methoxy-N*7*-(2-methoxyethyl)-N*7*-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide were combined to yield 1S,2S,3R,4R)-3-(5-Chloro-2-{1-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (82.19 mg, 41% yield) as a beige foam. Purification separated the compound into its corresponding enantiomers. 1H-NMR (CDCl3) δ 8.17 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 6.94 (d, J=7.7 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.36 (m, 1H), 6.32 (m, 1H), 5.62 (br s, 1H), 5.36 (br s, 1H), 4.36 (m, 1H), 3.73 (s, 3H), 3.45 (m, 2H), 3.35 (m, 4H), 3.07 (br s, 1H), 2.94 (br s, 1H), 2.77 (m, 2H), 2.60 (m, 2H), 2.50 (d, J=8.16 Hz, 1H), 2.25 (m, 5H), 2.15 (m, 2H), 1.31 (m, 2H). LC/MS (ESI+)=541 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:6][CH2:7][CH2:8][O:9][C:10]3[C:11]([O:24][CH3:25])=[CH:12][C:13]4[O:18][C:17](=[O:19])[C:16]5[CH2:20][CH2:21][CH2:22][C:15]=5[C:14]=4[CH:23]=3)[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccc(F)cc2)CC1)CCC3
Yield: 84 %

Procedure:
Method B (12 h at 55° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 1-(4-fluorophenyl)piperazine; yield 84%; fusion point 139°-141° C. (from ethanol). Fumarate: method E; yield 90%; fusion point 195°-200° C. (from ethanol).
Reaction SMILES: C([O:8][P:9]([O:19][C@H:20]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([CH:42]([NH:44]C(=O)OCC3C=CC=CC=3)[CH3:43])=[N:40][CH:41]=2)=[CH:32][CH:31]=1)[C@H:21]([NH:24][C:25](=[O:29])[CH:26]([F:28])[F:27])[CH2:22][F:23])([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C.O>[P:9]([OH:11])([OH:10])([O:19][C@H:20]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[N:40][C:39]([CH:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)[C@H:21]([NH:24][C:25](=[O:29])[CH:26]([F:28])[F:27])[CH2:22][F:23])=[O:8]
Reactant: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@@H](OP(=O)(OCc3ccccc3)OCc3ccccc3)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(N)c1ccc(-c2ccc([C@@H](OP(=O)(O)O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reaction time: 5 h
Yield: 91.4 %

Procedure:
Palladium on carbon (1:9, 23 mg, 0.022 mmol) is added to the product of step 4, Example 95A (235 mg, 0.308 mmol) in ethanol (5 mL) and water (1 mL). The mixture is evacuated with nitrogen three times and stirred under hydrogen for 5 hours. The reaction mixture is filtered through a 4 mL pad of solka flok and rinsed with alternating 4 mL rinses of ethanol and water ten times. The solvent is removed under reduced pressure to give the crude product, which is taken up in water (5 mL) and filtered through a 0.45 um filter disk, rinsing with water (2 mL). The filtrate is freeze dried to give the title product (126 mg): 1H NMR δ 8.75 (1H, s), 8.07 (1H, d), 7.63 (2H, d), 7.52-7.48 (4H, m), 6.00 (1H, t), 5.42 (1H, d), 4.82 (1H, dd), 4.64-4.43 (4H, m), 1.62 (3H, d); m/z: 447.12.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:59][N:60]1[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:65][C:62]2[CH:63]=[CH:64][N:60]([CH3:59])[N:61]=2)=[N:3][CH:4]=1
Reactant: Cn1ccc(N)n1
Reactant: COCCOc1ccc(Br)nc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Nc2ccn(C)n2)nc1
Yield: 35 %

Procedure:
2-Bromo-5-(2-methoxy-ethoxy)-pyridine (0.42 mmol), sodium-tert.-butylate (1.4 eq.), tris-(dibenzylidene-aceton)-dipalladium (0.1 eq.), BINAP [=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] (0.1 eq.) and 1-methyl-1H-pyrazole-3-amine (1.4 eq.) are filled under nitrogen in a microwave reaction vessel. Degassed toluene (45 eq.) is added. The reaction suspension is heated for 100 min to 120° C. and for 30 min to 150° C. Ethyl acetate is added to the reaction suspension and filtrated over celite. The solvent of the filtrate is removed in vacuo. [5-(2-Methoxy-ethoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine (“A22”) is obtained after reversed phase column chromatography (Water/acetonitrile+0.1% TFA) as yellow oil in a yield of 35%: HPLC (method C): 1.16 min; LC-MS (method A): 0.43 min, 249.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 10.803 (s, 1H), 7.900 (d, 1H, J=2.8 Hz), 7.802 (dd, 1H, J=2.8 Hz, J=9.4 Hz), 7.739 (d, 1H, J=2.3 Hz), 7.314 (d, 1H, J=9.4 Hz), 6.103 (d, 1H, J=2.3 Hz), 4.149-4.131 (m, 2H), 3.861 (s, 3H), 3.688-3.670 (m, 2H), 3.323 (s, 3H).
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.[C:11]([O:18]C=C)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:11]([O:18][C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=COC(=O)CCCCC
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: CCCCCC(=O)OC12C=CC(CC1)C2
Temperature: 160 °C
Reaction time: 30 h
Yield: 25 %

Procedure:
Vinyl hexanoate (100 ml) and dicyclopentadiene (15 ml) were brought to reflux under nitrogen (160° C.). Over a period of 24-36 h, a further 9 additions (each 15 ml) of dicyclopentadiene were made, and heating under reflux continued. During this time, the temperature of the boiling liquid increased until after the last addition it was about 205° C. Excess starting materials were then allowed to distil off. After cooling of the mixture to 50° C., methanol (200 ml) was added and the precipitate allowed to form and settle, cooling to 20° C. The ester solution was decanted off and the precipitate washed with a further batch of methanol (100 ml). The methanol solutions were combined and evaporated under reduced pressure at 40-50° C. to yield about 114 g crude norbornenyl hexanoate (estimated molar yield 25% based on the vinyl hexanoate). This material was suitable for biotransformation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8]([N:24]([O:25][CH3:26])[CH3:23])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncc(Br)cc1Cl
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.7 %

Procedure:
In N,N-dimethylformamide (24 mL) was dissolved 5-bromo-3-chloropyridine-2-carboxylic acid (2.36 g), 1-hydroxybenzotriazole (2.2 g) and 3-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.87 g), N,O-dimethylhydroxylamine hydrochloride (1.27 g) and triethylamine (1.95 mL) was added to the solution, and the resulting mixture was stirred at room temperature for 20 hours. Water was added to the obtained residue, extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated brine. After drying the mixture over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 5-bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.67 g).
Reaction SMILES: [H-].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[CH3:16].I[CH2:25][CH3:26]>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:25][CH3:26])[CH:18]=1)[CH3:16]
Reactant: C[C@@H](NCCCc1ccccc1Cl)c1cccc(O)c1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1cccc([C@@H](C)NCCCc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NPS R-568 (30.3 g 100 mmol) in dichloromethane at −78° C. was treated dropwise with borontribromide (50 g, 200 mmol). The reaction 40 was stirred 1 hr at rt and poured over ice. The hydrobromide was extracted from the aqueous phase with chloroform. The chloroform solubles were then washed (4×100 ml) with 50% HCl. The chloroform wash was dried over anhydrous magnesium sulfate and concentrated to afford (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride as a solid. A solution of sodium hydride (0.48 g, 20 mmol) in dimethylformamide was treated with (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride (3.25 g, 10 mmol) and the reaction stirred 1 hr at rt. The reaction was treated with iodoethane (1.71 g, 11 mmol) and stirred 16 hr at rt. Work-up and chromatography through silica using 3% methanol in chloroform afforded (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-ethoxyphenyl)ethylamine, 6T, as an oil; m/z (rel. int.) 316 (M+, 1), 302 (100), 282 (11), 196 (5), 178 (7), 149 (74), 121 (34), 103 (25), 91 (28), 77 (29).
Reaction SMILES: O[C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5](O)[CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH:15](O)[CH:16]([CH3:18])[CH3:17])[CH2:3]1.P(Cl)(Cl)([Cl:33])=O>N1C=CC=CC=1>[Cl:33][CH:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3]1
Reactant: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
To the solution of 3α,6α,24-trihydroxy-5β-cholestan (1.5 g) in pyridine (20 ml) was added phosphorus oxychloride (3 ml). After completion of the reaction, the reaction mixture was poured into ice-water and extracted with diethyl ether. The ether layer was washed with an aqueous solution of hydrochloric acid and then with water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel to give 0.6 g of 3-chlorocholest-5,24-diene.
Reaction SMILES: C([O:3][C:4](=[O:42])[C@H:5]([OH:41])[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C@@H:5]([OH:41])[C:4]([OH:42])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)[C@H](O)CNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of (R)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]-benzoylamino}-2-hydroxypropionic acid ethyl ester (0.60 g, 0.98 mmol) in ethanol (5 mL) and THF (5 mL) was stirred and 4 N sodium hydroxide (0.76 mL, 2.94 mmol) was added. The solution was stirred for 3 hours at room temperature and then acidified with 1 N hydrochloric acid. Evaporation in vacuo afforded an oil, which was partitioned between ethyl acetate, water and brine. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with water and brine. Drying (magnesium sulphate), filtration, and evaporation in vacuo afforded 0.43 g (73%) of the title compound as a solid.