Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9](Cl)=[CH:10][CH:11]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:15]>CO>[C:1]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([NH2:15])=[CH:10][CH:11]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2nc(Cl)ccc2[nH]1
Reactant: N
Solvent: CO
Product: CC(C)(C)c1cc2nc(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 10 h
Yield: 26 %

Procedure:
In a 500 mL autoclave, a solution of 2-tert-butyl-5-chloro-1H-pyrrolo[3,2-b]pyridine (5.0 g, 24 mmol) and CuSO4′5H2O (0.5 g, 2.0 mmol) in aqueous ammonia (200 mL) and CH3OH (100 mL) was heated at 180° C. (at this temperature, the pressure in the autoclave was about 2 MPa) and stirred for 10 hours. The mixture was allowed to cool down to room temperature. The solvent was removed by evaporation under vacuum. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by the preparative HPLC to give 2-tert-butyl-1H-pyrrolo[3,2-b]pyridin-5-amine (1.15 g, 26%). 1H NMR (CDCl3, 300 MHz) δ 10.63 (brs, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.23 (d, J=8.7 Hz, 1H), 5.86 (d, J=1.5 Hz, 1H), 5.40 (brs, 2H), 1.29 (s, 9H); MS (ESI); m/e (M+H+): 190.2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([NH:15][OH:16])=[NH:14].[O-2].[Mg+2].[C:19]1([S:25][CH2:26][C:27](Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([S:25][CH2:26][C:27]2[O:16][N:15]=[C:13]([CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])[N:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=C(CN1C(=O)c2ccccc2C1=O)NO
Reactant: O=C(Cl)CSc1ccccc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1noc(CSc2ccccc2)n1
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
To 10 g (0.046 mol) of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-hydroxy-acetamidine dissolved in 500 mL of DMF, 1.84 g (0.046 mol, 1 eq) of magnesium oxide were added. After 15 min, 8.5 g (0.046 mol, 1 eq) of phenylsulfanyl-acetyl chloride were added, and the temperature was raised to 105° C. and the solution was stirred overnight. The reaction mixture was partitioned between aqueous NH4Cl and EtOAc, dried over Na2SO4. Column chromatography on silica gel with EtOAc/Heptane 1:1 yielded 8.7 g (55%) of 2-(5-phenylsulfanylmethyl-[1,2,4]oxadiazol-3-ylmethyl)-isoindole-1,3-dione as a light yellow solid, MS: 352 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:13]=2)[CH:8]=1.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:24])[N:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1
Yield: 18.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-91, 0.350 g, 0.945 mmol), pivaloyl chloride (0120 g, 0.945 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.080 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 4.30 (d, J=6.3 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.61-7.64 (m, 2H), 8.06 (d, J=9.0 Hz, 1H), 8.19 (m, 1H), 8.58 (d, J=8.4 Hz, 1H), 9.32 (s, 1H), 12.82 (s, 1H); MS (m/z): 454.50 (M+H)+.
Reaction SMILES: [CH:1]1(/[C:7](/[CH3:14])=[CH:8]/[C:9](OCC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC>[CH:1]1(/[C:7](/[CH3:14])=[CH:8]/[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C(\C)C1CCCCC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C(=C\CO)C1CCCCC1
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of (E)-ethyl 3-cyclohexylbut-2-enoate (Appella et al. (1999), J. Am. Chem. Soc. 121:9473) (1 g, 5.09 mmol) in dry Et2O (10 mL) was added a solution of lithium aluminum hydride (5.10 mL, 5.10 mmol, 1 M in Et2O). After 5 minutes, the reaction mixture was neutralized by dropwise addition of THF solution followed by addition of a saturated solution of potassium sodium tartrate. The reaction mixture was stirred for 25 minutes, and then diluted with Et2O. The organic layer was separated and washed with water, dried over Na2SO4 and concentrated in vacuo to afford (E)-3-cyclohexylbut-2-en-1-ol as a colorless oil which was used directly in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][CH2:13][C:14](=[O:17])[CH2:15][CH3:16].Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([CH3:12])[C:14](=[O:17])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCC(=O)CC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)C(C)=Cc1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To 4-chlorobenzaldehyde 46a (99.6 mmol, 14 g) in water (44 mL) was added KOH (44.6 mmol, 2.5 g). The mixture was heated at 65° C. and 3-pentanone (99.6 mmol, 8.58 g) was added dropwise over 10 min. After refluxing for 8 h, the reaction mixture was cooled to room temperature and stirred overnight. Following addition of 260 mL 1N aqueous HCl, the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc/heptane) to give 8.59 g of 46b.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:6](Cl)[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:3]=1.C(N(CC)CC)C>C(O)C.[Pd]>[CH2:16]([C@H:13]1[CH2:12][CH2:11][C@H:10]([CH2:9][CH2:8][C:7]2[CH:6]=[N:5][C:4]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)=[N:3][CH:2]=2)[CH2:15][CH2:14]1)[CH2:17][CH3:18]
Reactant: CCC[C@H]1CC[C@H](CCc2c(Cl)nc(-c3ccc(F)c(F)c3)nc2Cl)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC[C@H]1CC[C@H](CCc2cnc(-c3ccc(F)c(F)c3)nc2)CC1
Yield: 67.2 %

Procedure:
This dichloropyrimidine compound (2.5 g) was then dissolved in ethyl alcohol (50 ml), followed by subjecting the solution to hydrogenation using 5% Pd/C (0.1 g) in the presence of triethylamine (1 ml), filtering off Pd/C catalyst after the absorption of hydrogen gas ceased, distilling off ethyl alcohol from the filtrate and recrystallizing a residue from ethyl acetate to obtain 5-[2'-(trans-4"-propylcyclohexyl)ethyl]-2-(3,4-difluorophenyl)pyrimidine (1.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:6]2[C:7]([CH3:13])=[N:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+]>COCCOCCOC>[F:40][C:36]([F:41])=[CH:11][C:10]1[CH:9]=[N:8][C:7]([CH3:13])=[C:6]2[O:14][C:2]([CH3:15])([CH3:1])[O:3][CH2:4][C:5]=12
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: Cc1ncc(C=C(F)F)c2c1OC(C)(C)OC2

Procedure:
A mixture of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde, 0.11 mole of triphenylphosphine and 0.11 mole of sodium chlorodifluoroacetate in 100 ml. of diglyme is heated under nitrogen at 90° for 24 hours. The reaction mixture is then filtered and concentrated in vacuo. Chromatography of the residue on silica gel and elution with ether-petroleum ether (10-50%) gives 5-(2,2-difluorovinyl)2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.CNCCCN=C=NCC.ON1C2C=CC=CC=2N=N1.O[N:37]=[C:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>CN(C)C=O>[N:1]1([C:6]2[CH:14]=[C:10]([C:11]3[O:13][N:45]=[C:38]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)[N:37]=3)[CH:9]=[N:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cncc(-n2cccc2)c1
Agent: CCN=C=NCCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: c1cncc(-c2noc(-c3cncc(-n4cccc4)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-(1H-pyrrol-1-yl)nicotinic acid (Maybridge, 188 mg, 1.00 mmol) in dimethylformamide (anhydrous, 5 mL) was added N-(3-methylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (Aldrich, 192 mg, 1.00 mmol) and 1-hydroxybenzotriazole (HOBT) hydrate (Fluka, 153 mg, 1.00 mmol). The mixture was stirred at ambient temperature for 20 minutes. N′-Hydroxynicotinimidamide (137 mg, 1.0 mmol) was added and the mixture was stirred for 6-10 hours, and then warmed to 140° C. for 2-4 hours. The reaction was cooled to ambient temperature and triturated with water (10 mL). The precipitate was filtered and dried under vacuum to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 6.34-6.44 (m, 2H), 7.60-7.82 (m, 3H), 8.50 (dt, J=8.1, 1.9 Hz, 1H), 8.71 (dd, J=2.5, 1.9 Hz, 1H), 8.84 (dd, J=4.6, 1.5 Hz, 1H), 9.21 (d, J=1.7 Hz, 1H), 9.26 (d, J=2.4 Hz, 1H), 9.31 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]1[C:7]([CH:12]=O)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]1[C:7]([CH2:12][N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][S:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[F:14])=[O:22])[CH2:25][CH2:26]2)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: O=S(CC1CCNCC1)c1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1CN1CCC(CS(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
After then dissolving 44 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 49 mg of the 4-[(2-fluorophenylsulfinyl)methyl]piperidine in 2 ml of dichloromethane, 65 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate/methanol) to obtain the title compound (43 mg, 52% yield).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:18]/[C:19](=[C:22](/[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH2:36][CH3:37])[O:30][C:29]([CH3:39])([CH3:38])[CH:28]=[C:27]2[CH:40]([CH3:42])[CH3:41])\[CH3:23])/[CH:20]=O>>[F:18]/[C:19](=[C:22](/[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH2:36][CH3:37])[O:30][C:29]([CH3:39])([CH3:38])[CH:28]=[C:27]2[CH:40]([CH3:41])[CH3:42])\[CH3:23])/[CH:20]=[CH:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (159 mg, 0.60 mmol) and (2E)-2-fluoro-3-(4-isopropyl-2,2-dimethyl-7-propoxy-2H-chromen-6-yl)but-2-enal (Compound 99, 72 mg, 0.21 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [Na].COC(=O)CC[S:7][C:8]1[C:17]([C:18](=[O:26])[NH:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>CO>[SH:7][C:8]1[C:17]([C:18]([NH:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[O:26])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: COC(=O)CCSc1nc2ccccc2cc1C(=O)NCc1cccs1
Agent: [Na]
Solvent: CO
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1S
Temperature: 70 °C
Yield: 90 %

Procedure:
600 mg (26.1 mmol) sodium were added slowly to MeOH (500 ml). Then a solution of 1.16 g (3.0 mmol) 3-[[3-[oxo-(2-thienylmethylamino)methyl]-2-quinolyl]-thio]propanoic acid methyl ester (Example 2) in MeOH (60 ml) was added at RT. Then the reaction solution was heated for 1 h at 70° C. After cooling to RT the mixture was concentrated to small volume under vacuum. The residue was taken up with water and the solution was washed with EE. Then it was acidified with concentrated hydrochloric acid to pH 3. The deposit formed was filtered off and dried. 805 mg (2.7 mmol, 90%) 2-mercapto-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide were obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:12]1([C:18](OC)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+].[NH4+].[Cl-]>CCOCC.O>[CH2:7]([C:12]1([CH2:18][OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC1(C(=O)OC)CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCCC1(CO)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
LiAlH4 (15 mL, 30 mmol, 2 M/THF) was added drop wise to a solution of 2-2 (1.773 g, 12.5 mmol) in ether (9 mL) at a rate to maintain a gentle reflux. The mixture was stirred further for 15 min. and then was cooled to 0° C. H2O (1 mL) was added followed by 3 M NaOH (1.2 mL) and more H2O (3 mL). The resulting mixture was allowed to warm to room temperature and after 1 h of stirring, 50 mL saturated NH4Cl solution was added. The mixture was extracted with dichloromethane (3×30 mL) and the combined dichloromethane solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a combiflash system by Teledyne Isco (80 g silica gel, 0→100% ethyl acetate/hexanes) which gave the title compound (968 mg, 5.3 mmol, 42%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br.[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[C:18](=[O:32])[CH2:17]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22]2)[C:18]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])([OH:32])[CH2:17]1
Reactant: Fc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)CC(=O)C2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
94.4 cm3 of a 1.6M solution of butyllithium in hexane are added dropwise to a solution of 16.5 cm3 of 2-fluorobromobenzene in 200 cm3 of tetrahydrofuran, cooled to -78° C. The reaction mixture is stirred at -78° C. for 2 hours, and then a solution of 8.1 g of (3aRS,6SR,7aSR)-6-hydroxymethyl-2-tert-butyloxycarbonylperhydroisoindol-4-one in 20 cm3 of tetrahydrofuran is added. The reaction mixture is subsequently stirred at room temperature for 48 hours, then treated with 50 cm3 of saturated aqueous ammonium chloride solution and subjected to extraction with 200 cm3 of ethyl acetate, and the organic phase is washed with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 75 cm3. Fractions 21 to 45 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.35 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-tert-butyloxycarbonylperhydroisoindol 4-ol are obtained in the form of a thick white foam.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:14]#[N:15])=[CH:3][CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: Brc1ccc(Br)c2ccccc12
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)c2ccccc12
Temperature: 125 °C
Yield: 33 %

Procedure:
A mixture of 1,4-dibromonaphthalene (24.06 g, 84 mmol) and copper cyanide (6.02 g, 67 mmol) in DMF (85 mL) was heated to 125° C. overnight. The mixture was partially concentrated to remove DMF and the resulting residue washed with aqueous ammonium hydroxide and extracted with ethyl acetate. The organic layer was concentrated and purified by chromatography to yield 4-bromo-1-naphthonitrile (5.13 g, 26%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:19])=[C:6]([CH:13]([O:17][CH3:18])[C:14]([OH:16])=O)[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1)[CH3:2].[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:21]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14](=[O:16])[CH:13]([C:6]2[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=2[F:19])[O:17][CH3:18])=[CH:24][CH:23]=1)#[N:20]
Reactant: CCOc1cc(OCC)c(F)c(C(OC)C(=O)O)c1
Reactant: N#Cc1ccc(CN)cc1
Product: CCOc1cc(OCC)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-(3,5-Diethoxy-2-fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3,5-diethoxy-2-fluoro-phenyl)-2-methoxy-acetamide. Light yellow oil. MS 387.3 ([M+H]+)
Reaction SMILES: [CH3:1][SH:2].[H-].[Na+].[C:5]([C:7]1([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](F)[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:6].O>CN(C=O)C>[C:5]([C:7]1([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([S:2][CH3:1])[CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:6]
Reactant: N#CC1(c2cc(F)cc(F)c2)CCOCC1
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(F)cc(C2(C#N)CCOCC2)c1
Temperature: 100 °C

Procedure:
Methanethiol was bubbled into a stirred suspension of sodium hydride (65% w/w dispersion in mineral oil, 273 mg, 7.4 mmol) in DMF (10 ml) until a clear solution was obtained. 4-Cyano-4-(3,5-difluorophenyl)-3,4,5,6-tetrahydro-2H-pyran (1.65 g, 7.4 mmol) was added and the resulting mixture was heated at 100° C. for 22 h, cooled and poured into water (100 ml). The mixture was extracted with Et2O (100 ml) and extract washed with water (100 ml), brine (100 ml) and dried (MgSO4). Removal of solvent gave 1.87 g (quant.) of the titled compound as a tan oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)=[C:4]([Cl:14])[CH:3]=1.[NH:15]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].O.O1CCOCC1>[Cl:14][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[N:15][NH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1
Reactant: Nc1nnc(-c2ccc(Br)cc2Cl)s1
Reactant: OB(O)c1cn[nH]c1
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: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccc(-c3cn[nH]c3)cc2Cl)s1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (500 mg, 1.721 mmol), 4-pyrazole boronic acid pinacle ester (668 mg, 3.44 mmol), cesium carbonate (1.68 g, 5.16 mmol), Pd2(dba)3.CH2Cl2 (178 mg, 0.172 mmol), and Xphos (82 mg, 0.172 mmol), followed by addition of 1,4-dioxane (2 mL)/H2O (0.5 mL). The vial was purged with N2 3 times and the reaction mixture was heated via microwave irradiation at 100° C. for 1 h. The reaction mixture was filtered through a disposable filter funnel, washed with EtOAc, concentrated in vacuo, and purified by silica gel chromotography (2% to 15% MeOH/DCM) to afford 5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine (250 mg, MS: 278.0 [M+H+].)
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:60]([C@@H:62]1[CH2:71][C@H:70]([NH2:72])[C:69]2[C:64](=[CH:65][CH:66]=[C:67]([C:73]([F:76])([F:75])[F:74])[CH:68]=2)[NH:63]1)[CH3:61].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[N:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:72][C@@H:70]3[C:69]4[C:64](=[CH:65][CH:66]=[C:67]([C:73]([F:76])([F:74])[F:75])[CH:68]=4)[NH:63][C@H:62]([CH2:60][CH3:61])[CH2:71]3)=[N:7][CH:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC[C@@H]1C[C@H](N)c2cc(C(F)(F)F)ccc2N1
Reactant: Brc1ccc(N2CCOCC2)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](Nc2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-(6-Bromo-pyridin-3-yl)-morpholine (3.16 g), tris(dibenzylideneacetone)-dipalladium (806 mg), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.2 g) were dissolved in toluene (60 ml) and the mixture was stirred under nitrogen atmosphere at 50° C. for an hour. The reaction mixture was cooled to room temperature, thereto was added the compound obtained in Example 8 (1) dissolved in toluene (10 ml) and the mixture was stirred at room temperature for 15 minutes. The stirring was further continued at 50° C. overnight after addition of sodium tert-butoxide (1.86 g). Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo to give the titled compound. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give the titled compound (1.1 g). MS (m/z): 407 [M+H]+.
Reaction SMILES: [Cr](O)(O)(=O)=O.[CH2:6]([C@:9]12[CH2:17][CH2:16][C@@H:15]3[C@@H:18]4[C:23]([CH2:24][CH2:25][C@H:14]3[C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[OH:26])=[CH:22][CH2:21][CH2:20][CH2:19]4)[CH2:7][CH3:8]>CC(C)=O>[CH2:6]([C@:9]12[CH2:17][CH2:16][C@@H:15]3[C@@H:18]4[C:23]([CH2:24][CH2:25][C@H:14]3[C@@H:13]1[CH2:12][CH2:11][C:10]2=[O:26])=[CH:22][CH2:21][CH2:20][CH2:19]4)[CH2:7][CH3:8]
Reactant: CCC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O

Procedure:
Add 8N chromic acid dropwise with stirring to a solution of 13β-n-propyl-gon-4-en-17β-ol in acetone (100 cc.) until the solution becomes permanently orange. Add isopropanol (10 cc.) and potassium carbonate (5 g.), filter and evaporate the filtrate to dryness. Filter the residue in benzene-ether (1:1) through neutral alumina (20 g.), evaporate and recrystallize the product from methanol to obtain 13β-n-propyl-gon-4-en-17-one. Recrystallize from ether-hexane to obtain the pure product, m.p. 89°-90° C.