Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][CH2:21][O:22][CH3:23])[CH:7]=[O:8]
Reactant: COCCBr
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1c(Br)cc(C=O)cc1OC
Temperature: 75 °C

Procedure:
To a 500 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 5-bromovanillin (10 g, 43.28 mmol), DMF (125 mL), powdered Cs2CO3 (28.2 g, 86.56 mmol) and 2-bromoethylmethyl ether (5.08 mL, 54.10 mmol). This well stirred mixture was heated at 75° C. for 24 h. The cooled mixture was filtered through a frit to remove the cesium salts and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. 1H NMR (CDCl3): δ3.44 (s, 3H); 3.77 (t, j=4 Hz, 2H); 3.92 (s, 3H); 4.27 (t, j=4 Hz, 2H); 7.38 (d, j=2 Hz, 1H); 7.65 (d, j=2Hz, 1H); 9.84 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Cc1cccc(B(O)O)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1C
Yield: 47.9 %

Procedure:
2,3-Dimethylphenylboronic acid (39 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (28 mg, 48%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)nc3)cc2)CC1
Yield: 76.1 %

Procedure:
The title compound (0.34 g, 75%) was prepared as a white solid from 4-[6-(methylsulfonyl)-3-pyridinyl]phenol (0.25 g, 1.00 mmol), N-Boc-4-piperidinemethanol (0.23 g, 1.00 mmol) and Ph3P (0.27 g, 1.00 mmol) in THF (6 mL) followed by diisopropyl azodicarboxylate (0.22 g, 94%, 1.0 mmol) in THF (2 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CD3OD): δ 8.96 (d, 1H, J=2.2 Hz), 8.28 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 8.10 (d, 1H, J=8.1 Hz), 7.70 (d, 2H, 8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 4.20-4.10 (m, 2H), 3.92 (d, 2H, J=6.1 Hz), 3.24 (s, 3H), 2.90-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (2H); LRMS (APCI), m/z 469 (M+Na).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:25][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 91 step E from 6-chloro-4-(3-chloro-phenyl)-2-piperidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (70 mg, 0.15 mmol) and 4N HCl in dioxane. Off white solid (40 mg, 65%). LC-MS (ESI): 401 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:25]1([N:31]=[C:32]=[S:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:25]1([NH:31][C:32]([N:21]2[CH2:20][CH2:19][C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[CH:16][CH:17]=3)[CH2:22]2)=[S:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: S=C=Nc1ccccc1
Reactant: c1cc(N2CCC(COc3ccc4c(c3)CNCC4)CC2)ccn1
Solvent: ClCCl
Product: S=C(Nc1ccccc1)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline (30 mg) in methylene chloride (0.5 ml) was added phenyl isothiocyanate (0.012 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1, 1% triethylamine) and dried under reduced pressure to give the title compound (40 mg).
Reaction SMILES: [Na].[CH3:2][CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1)[CH2:4][CH3:5].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:2][CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:9][CH:8]=1)[CH2:4][CH3:5]
Reactant: Clc1ccccn1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Agent: [Na]
Product: CCC(C)Oc1ccc(OCCOc2ccccn2)cc1

Procedure:
In the same manner, the sodium salt of 2-[4-(1-methylpropoxy)phenoxy]ethanol and 2-chloropyridine are reacted together to give 2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 288} (M+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)(Cl)Cl>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (45 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 29 mg of 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 562.4 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.32 (m, 4 H) 1.36-1.52 (m, 2 H) 1.58 (d, J=12.91 Hz, 2 H) 1.65-1.84 (m, 1 H) 2.07 (d, J=10.56 Hz, 4 H) 2.99-3.17 (m, 3 H) 3.23 (t, J=10.76 Hz, 2 H) 3.35 (br. s., 2 H) 3.64 (br. s., 1 H) 3.72-3.89 (m, 2 H) 4.34 (t, J=4.89 Hz, 2 H) 6.32-6.47 (m, 1 H) 6.49-6.65 (m, 1 H) 6.67-7.10 (m, 2 H) 7.49 (d, J=9.00 Hz, 1 H) 8.03 (s, 1 H) 8.75 (d, J=3.91 Hz, 1 H)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Li][CH2:11][CH2:12][CH2:13][CH3:14].O>CCOCC>[Br:9][C:4]1[CH:3]=[C:2]([C:12]2[CH2:13][C:14]3[C:6]([CH:11]=2)=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Brc1cc(Br)cc(C2=Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 12.6 g (40.0 mmol) of 1,3,5-tribromobenzene in 400 ml of ether, 160 ml (40.0 mmol) of 0.25 M nBuLi in hexanes was added for 1 h at −80° C. The mixture was stirred for 1.5 h at this temperature, and then a solution of 5.29 g (40.0 mmol) of indanone-2 in 200 ml of ether was added dropwise over 1 hour while vigorously stirring. The reaction mixture was allowed to warm to room temperature and it was stirred at this temperature for 24 h. Then, 100 ml of water was added. The organic layer was separated; the aqueous layer was extracted with 3×50 ml of dichloromethane. The combined organic layers were dried over Na2SO4 and then evaporated to dryness. The residue was dissolved in 250 ml of toluene, and 0.75 g of p-TosOH was added. The resulting solution was refluxed for 1 hours using a Dean-Stark trap to remove the water formed. Next, the mixture was evaporated to dryness, and the product was isolated by flash-chromatography on Silica Gel 60 (d 50 mm, l 400 mm, eluent: hexanes). Yield 8.54 g (61%) of white powder.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:20])C(=O)C1>CN(C)C=O>[Br:20][C:4]1[CH:5]=[CH:6][C:1]([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])=[CH:2][CH:3]=1
Reactant: C[C@@H](CC#N)Nc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: C[C@@H](CC#N)Nc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
(3S)-3-(Phenylamino)butanenitrile (for a preparation see Intermediate 105) (11.3526 g, 70.9 mmol) was taken up in N,N-dimethylformamide (DMF) (200 mL) under nitrogen and cooled in an ice-bath. NBS (12.61 g, 70.9 mmol) was added and the reaction stirred. After 20 min, the reaction was partitioned between EtOAc (1000 mL) and water (500 mL). The organic layer was washed with 2M NaOH×2, water and brine (500 mL each) and then dried with Na2SO4, filtered and concentrated to yield the product as a cream solid (17.3 g).
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])(=O)C.N>>[SH:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9]
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)CCCSC(C)=O)C1
Agent: N
Product: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)CCCS)C1

Procedure:
Hydrolysis of (cis)-1-(4-acetylthio-1-oxobutyl)-4-methoxy-L-proline with an aqueous ammonia solution according to the procedure of Example 2 yields 1-(4-mercapto-1-oxobutyl)-cis-4-methoxy-L-proline.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(O)=O.[Br:14]Br.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:14][C:7]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: BrBr
Reactant: Cc1ccccc1C#N
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(Br)cc1C#N
Temperature: 50 °C
Yield: 82.8 %

Procedure:
117 g (998 mmol) of 2-methylbenzonitrile was dropped to 1000 g of a Na-X type zeolite dried powder (Zeolam type F-9 manufactured by Toyo Corp.; 100 mesh or less) while stirring under air cooling. The resulted mixed was allowed to cool, and after cooled to 50° C. or lower, to this was added 213 g (1.33 mol) of bromine, and the mixture was stirred at 80 to 85° C. for 1.5 hours, then, cooled to 15° C. or lower. This was added into mixture of 100 g of potassium carbonate, 500 ml of water and 2 L of methanol at 10° C. or lower. The mixture was stirred for 0.5 hours, then, filtrated. The filtrated residue, zeolite powder was washed with 90% methanol water (2.2L×2), the filtrate and washed solution were combined, and concentrated until the total liquid quality reached 750 ml. The resulted while crystal was filtrated, and the crystal was washed with water to obtain 162 g (826 mmol) of 5-bromo-2-methylbenzonitrile.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:25])[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[CH:9][CH:10]=2)[O:5]1.Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][O:24][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=3)[CH2:13][C:4]([CH3:25])([CH3:3])[O:5]2)=[CH:10][CH:9]=1)#[N:29]
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Temperature: 60 °C

Procedure:
Sodium hydride (0.93g, 80% dispersion in oil) was added to a solution of 2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman-7-ol (containing 1 mole of carbon tetrachloride of crystallisation) (7.5g) in dimethylformamide (25 ml). Chloroacetonitrile (1.76g) was added and the mixture heated at 60° C for 3 hours. The solvent was removed under reduced pressure and the resulting oil was poured into water. The aqueous solution was extracted with ether and the etheeal extracts were dried (MgSO4) and evaporated under reduced pressure to yield an oil. Chromatography on alumina with ether-petrol (40°-60° C), 1:3 as eluate gave the title compound which crystallised on standing.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18])(=[O:27])[CH3:26]
Reactant: CCOC(=O)n1c(C(=O)c2cncnc2)c(N)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cncnc2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 3-amino-6-chloro-1-ethoxycarbonyl-2-(5-pyrimidinylcarbonyl)indole (step 2) and acetyl chloride.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=2)[CH:22]=[CH:23][CH:24]=1>ClCCl>[N:31]([C:27]1[CH:26]=[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[N:30]=[CH:29][N:28]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cccc(-c2cc(N)ncn2)c1
Solvent: ClCCl
Product: COc1cccc(-c2cc(N=C=S)ncn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.970 g, 4.17 mmol) in dichloromethane at room temperature was added 6-(3-methoxyphenyl)pyrimidin-4-amine (0.7 g, 3.48 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak as a major peak. The deep orange solution was concentrated and the remaining residue was filtered. The filtrate was purified by silica gel chromatography (0-10% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.39 g, 4.31 mmol, 46% yield) as a yellow oil. LCMS R.T.=2.91; [M+H]+=244.03.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2].[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+].C(COC)OC>O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[CH:8][C:9]=1[C:10]#[N:11])(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(=O)Nc1sc(Br)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1sc(-c2ccc(C#N)cc2)cc1C#N
Temperature: 80 °C
Yield: 86.2 %

Procedure:
2-Acetylamino-5-bromo-3-cyanothiophene (500 mg), 4-cyanophenylboronic acid (360 mg) and potassium carbonate (845 mg) were added to dimethoxyethane (15 ml) and water (2 ml) and the system purged with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (236 mg) was added and the mixture heated at 80° C. for 3.25 h. The mixture was cooled, concentrated under reduced pressure to remove most of the dimethoxymethane, dichloromethane added and the mixture filtered to give the product as a pale brown solid (470 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NC2CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (150 mg, 0.37 mmol) was dissolved in methylene chloride (3 ml) at 0° C., and triethyl amine (0.05 ml, 1.11 mmol) and cyclopropyl amine (0.03 ml, 0.56 mmol) were slowly added thereto. The resulting solution was stirred at room temperature for 3 hours, quenched with saturated ammonium chloride solution, extracted with ethyl acetate and filtrated with magnesium sulfate. The crude solution was evaporated and dried under a reduced pressure, to obtain 5-(4-chlorophenyl)-N-cyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, which are not further purified. The resulting product was dissolved in benzene (3 ml), and phosphorus pentachloride (85 mg, 0.41 mmol) was added thereto at room temperature. The solution was stirred for 20 minutes, hydroazoic acid (1.0 ml, 2.0 M solution in benzene) was added thereto and maintained room temperature for overnight. For completion of the reaction, reaction solution was refluxed for 10 minutes and purified by reverse phase preparative HPLC, to obtain the title compound (83 mg, 50%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:12](=[O:15])(=[O:14])=[O:13]>ClCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)=O
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(Cl)C(c1cccc(Cl)c1)S(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-chlorophenylacetyl chloride (1.89 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloroethane at 0° C. The mixture was stirred at room temperature for eighteen hours and evaporated, νmax. (CH2Cl2) 1790 cm-1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)[CH3:20].O>CN(C)C=O>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:27])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(C)=O)cc1OC
Reaction time: 17.5 h
Yield: 98.1 %

Procedure:
Acetovanillone (16.6 g, 0.10 mol), potassium carbonate (30.0 g, 0.22 mol) and ethyl-4-bromobutyrate (17 mL, 0.12 mol) were combined in dimethylformamide (50 mL) and stirred under Argon for 17.5 h. The reaction was poured into water (800 mL) and stirred for 24 h. The product was isolated by filtration to yield ethyl 4-(4-ethanoyl-2-methoxyphenoxy)butanoate (27.5 g, 98%) as a white powder. 1H NMR (δ, ppm): 1.28 (t, CO2CH2CH3), 2.21 (p, ArOCH2CH2CH2), 2.56 (t, ArOCH2CH2CH2), 2.60 (s, ArCOCH3), 3.92 (s, ArOCH3), 4.13 (t, ArOCH2), 4.18 (q, CO2CH2), 6.92 (d, aromatic H ortho to ArOCH2), 7.54 (s, aromatic H ortho to ArOCH3), 7.58 (d, aromatic H ortho to ArCOCH3).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:14].O>P(Cl)(Cl)(Cl)=O>[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[C:13]1[O:14][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N:12]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)c1O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(C3CCCN3C(=O)OCc3ccccc3)oc12
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)pyrrolidine-1-carboxylate (400 mg, 1 mmol) in phosphoryl trichloride (5 mL) was heated to reflux for 40 mins. The mixture was cooled to room temperature and poured into water (100 mL) carefully with vigorous stirring, then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=30:1 to 8:1) to give methyl 2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)benzo[d]oxazole-7-carboxylate (170 mg, yield 45%). LC-MS (ESI) m/z: 381 (M+1).
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C@H:12]([CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH3:36])[CH:25]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])(O)=[O:2].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C@H:43]([NH2:45])[CH3:44])[CH:38]=1>>[C:17]([O:16][C:14](=[O:15])[CH2:13][C@H:12]([C:10]([NH:9][C@H:4]([C:1]([NH:45][C@@H:43]([C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)[CH3:44])=[O:2])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:26]([CH3:36])[CH:25]=1)([CH3:18])([CH3:20])[CH3:19]
Reactant: C[C@@H](N)c1cccnc1
Reactant: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C)ccc1-c1ccccc1
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2cccnc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 89.5 %

Procedure:
According to the method of Example 25(a), tert-butyl (3R)-3-({[(1S)-1-(carboxy)-2,2-dimethylpropyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hexanoate (Preparation 19c)(497 mg, 1.0 mmol) was reacted with (R)-(+)-1-(3-pyridyl)ethylamine (122 mg, 1.0 mmol) at room temperature for 2.5 h, followed by the same work up and purification by flash chromatography (gradient elution with hexane:ethyl acetate 4:1 to 100% ethyl acetate) gave tert-butyl-(3R)-3-({[(1S)-2,2-dimethyl-1-{[(1R)-1-(3-pyridyl)ethylamino]carbonyl}propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]-hexanoate (537 mg, 89%) as a colourless foam.