Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C[CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])(OCC)=O.CNC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O.ClC[C:52]([O:54][CH2:55][CH3:56])=[O:53].CCN(C(C)C)C(C)C>CN(C=O)C>[C:52]([CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:54][CH2:55][CH3:56])=[O:53]
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCOC(=O)CCl
Agent: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 13c was prepared by the same procedure as described for the preparation of 13a using 4a (415 mg, 1.41 mmol), ethyl chloroacetate (207 mg, 0.18 mL, 1.68 mmol), DIEA (91 mg, 0.12 mL, 0.70 mmol), and DMF (5 mL): yield 204 mg (38%), MS: m/z 381 (M+H)+; 1HNMR (DMSO-d6) δ 8.06 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.73 (d, 1H, H-1′, J1′,2′=5.4 Hz), 5.33 (bd, 1H, OH-2′, J2′-2′OH=4.7 Hz), 5.19 (bd, 1H, OH-3′, J3′-3′OH=4.9 Hz), 5.03 (ddd, 1H, H-2′, J1′,2′=5.4 Hz, J2′,3′=5.7 Hz, J2′-2′OH=4.7 Hz), 4.17 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.4 Hz, J3′-3′OH=4.9 Hz), 4.02 (q, 2H, OCH2CH3), 3.92-3.99 (m, 1H, H-4′), 3.27 (bs, 2H, N(CH3)—CH2), 2.83-2.90 (m, 1H, 5′-CH2), 2.70-2.79 (m, 1H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.31 (s, 3H, N—CH3), 1.13 (t, 3H, OCH2CH3); UV λmax, nm, pH 1, 258.9 (∈ 16,100), pH 7, 260 (∈ 15,900), pH 13, 260.1 (∈ 16,200). Anal. (C16H24N6O5.0.5CHCl3.0.3CH3OH) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:34]1[CH:35]=[CH:36][N:37]=[C:38]2[C:43]=1[N:42]=[CH:41][C:40]([O:44][CH3:45])=[CH:39]2>CN(C=O)C.O>[CH3:45][O:44][C:40]1[CH:39]=[C:38]2[C:43]([C:34]([O:26][C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][N:11]=4)=[CH:25][CH:24]=3)=[CH:35][CH:36]=[N:37]2)=[N:42][CH:41]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: COc1ccc(-c2nnc(Nc3ccc(O)cc3)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 5 mL microwave tube was charged with 4-(4-(4-methoxyphenyl)phthalazin-1-ylamino)phenol and 3 equivalents of cesium carbonate (342 mg, 1.048 mmol) in 1.8 mL of DMF. The mixture was stirred at RT for 10 min. Following addition of 8-chloro-3-methoxy-1,5-naphthyridine (88 mg, 0.454 mmol), the vessel was capped and irradiated at 150° C. for 15 min in the microwave, at which time the reaction was determined complete by LC/MS. The mixture was cooled to ambient temperature and diluted with water. The solids were filtered and washed with water. The solids were triturated with methanol, filtered to remove remaining impurities, washed with additional methanol and dried under vacuum to afford N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-methoxyphenyl)phthalazin-1-amine as a light orange solid. MS [M+H]=502; Calc'd 501.54 for C30H25N5O3.
Reaction SMILES: [ClH:1].COC[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:16]1[CH2:19][NH:18][CH2:17]1.C1(C(C2C=CC=CC=2)N2C[CH:29]([O:31]C3C4C(=CC=CC=4)C=CC=3COC)C2)C=CC=CC=1>>[ClH:1].[CH3:29][O:31][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:16]1[CH2:17][NH:18][CH2:19]1
Reactant: COCc1ccc2ccccc2c1OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COCc1ccc2ccccc2c1OC1CNC1
Agent: Cl
Product: COc1ccc2ccccc2c1OC1CNC1

Procedure:
3-[(2-(Methoxymethyl)-1-naphthalenyl)oxy]-azetidine hydrochloride, mp 127° C. starting from 1-(diphenylmethyl)-3-[(2-(methoxymethyl)-1-naphtalenyl)oxy]-azetidine.
Reaction SMILES: C[O:2][C:3](=[O:63])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][N:31]([C:33]4[CH:38]=[CH:37][C:36]([C@H:39]5[CH2:56][C@@:54]6([CH3:55])[C@@H:50]([CH2:51][CH2:52][C@:53]6([OH:60])[C:57]#[C:58][CH3:59])[C@H:49]6[C:40]5=[C:41]5[C:46]([CH2:47][CH2:48]6)=[CH:45][C:44](=[O:61])[CH2:43][CH2:42]5)=[CH:35][CH:34]=4)[CH3:32])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:62])[CH2:10][CH2:9]1)[CH3:7].[C:64]([O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][C:75]([O:77][CH2:78]Cl)=[O:76])=[O:70])([CH3:67])([CH3:66])[CH3:65].[CH:80](N(C(C)C)CC)(C)C.[Na+].[I-]>C(#N)C>[CH3:80][CH:4]([CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:29][CH2:30][N:31]([C:33]4[CH:38]=[CH:37][C:36]([C@H:39]5[CH2:56][C@@:54]6([CH3:55])[C@@H:50]([CH2:51][CH2:52][C@:53]6([OH:60])[C:57]#[C:58][CH3:59])[C@H:49]6[C:40]5=[C:41]5[C:46]([CH2:47][CH2:48]6)=[CH:45][C:44](=[O:61])[CH2:43][CH2:42]5)=[CH:35][CH:34]=4)[CH3:32])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[O:62][CH2:78][O:77][C:75](=[O:76])[CH2:74][CH2:73][CH2:72][NH:71][C:69]([O:68][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:70])[CH2:10][CH2:9]1)[CH3:7])[C:3]([OH:2])=[O:63]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)OCCl
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]45)cc3)C[C@@]21C
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCOC(=O)CCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C

Procedure:
The compound of Example 1I (1 mmol) is combined with an equimolar amount of the compound of Example 11A in 1 mL of acetonitrile. Diisopropylethylamine (2 eq) and NaI (20 mg) are added, and the resultant mixture is heated at 90 C for 20 hrs. The reaction mixture is partitioned between ethyl acetate and water; the organic extract is washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is purified on silica gel using a gradient of ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:18][CH2:17][C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1)=O.ClS([N:25]=[C:26]=[O:27])(=O)=O.CO.C[O-].[Na+]>ClCCl>[CH2:17]1[C:9]2=[C:10]([C:26]([NH2:25])=[O:27])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5][CH2:18]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(N1CCc2cc3ccccc3n2CC1)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1c2n(c3ccccc13)CCNCC2
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl)-1-ethanone (448 mg, 1.6 mmol) in dichloromethane (20 mL) is treated with chlorosulfonyl isocyanate (0.19 mL, 2.1 mmol). The resulting golden homogenous solution is stirred for 1 hour and treated with methanol (10 mL) and a solution of 25% sodium methoxide in methanol (2 mL, 8.8 mmol). The reaction mixture quickly turns to a white suspension and after 30 min is filtered to give a crude white solid. This material is triturated with hot methanol, filtered through a pad of celite, and concentrated to 184 mg of a white solid that is further purified by LC (230-400 silica gel) eluting with 9:1:89 methanol/NH4OH/dichloromethane to afford 137 mg of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole-11-carboxamide as a white solid. IR (drift) 3353, 3341, 3173, 1641, 1602, 1549, 1463, 1432, 1418, 1322, 1314, 778, 740, 729, 654 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]([Cl:21])=[CH:18][CH2:19]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:19][CH:18]=[C:17]([Cl:21])[Cl:16])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: ClCC=C(Cl)Cl
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Cl)Cl)Cc1ccc(Cl)cc1
Yield: 66 %

Procedure:
Using 0.50 g of (4-chlorobenzyl)malononitrile, 5 ml of N,N-di-methylformamide, 0.12 g of sodium hydride (60% in oil), and 0.30 ml of 1,1,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 0.52 g of 2-(4-chlorobenzyl)-2-(3,3-dichloro-2-propenyl)malononitrile (the present compound (20)).
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][CH:9]=1)(C)(C)C.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=1)C(O)=O.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH2:46][CH2:47]O)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH2:46][CH2:47][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:6](=[O:19])[C:23]3[CH:27]=[C:28]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)[CH:29]=[C:21]([F:20])[CH:22]=3)=[CH:9][CH:10]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: COc1ccc(CCO)cc1OC
Product: COc1ccc(CCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)cc1OC

Procedure:
Compound is prepared from tert-butyl(4-hydroxy-1-naphthyl)carbamate, 3-fluoro-5-piperidin-1-yl-benzoic acid and 2-(3,4-Dimethoxy-phenyl)-ethanol according to conditions described in general procedure D. A deep pink solid is produced (42 mg). Mp: 158-160° C.; 1H NMR (300 MHz, CDCl3) δ 1.60-1.68(m, 6H), 3.00(d, J=6.3 Hz, 1H), 3.18-3.27(m, 5H), 3.85-3.87(m, 6H), 4.35(d, J=6.6 Hz, 1H), 4.48(d, J=7.2 Hz, 1H), 6.71-6.91(m, 4H), 6.98(d, J=7.8 Hz, 1H), 7.08(d, J=8.4 Hz, 1H), 7.30-7.34(m, 1H), 7.46-7.56(m, 2H), 7.69(d, J =7.8 Hz, 1H), 7.82(d, J=7.8 Hz, 1H), 7.94(s, 1H), 8.33(d, J=9.0 Hz, 1H); MS 529 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)C=Cc1ccc(Br)s1
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: COCCOC
Product: O=C(O)C=Cc1ccc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1 g (4.3 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 247 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred at room temperature for 10 min. 0.900 g (6.4 mmol) of 4-fluoro -phenylboronic acid and 4 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. Yield: 500 mg.
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[F:18])=[C:5]([OH:21])[CH:4]=1)[CH3:2].[CH3:22]CN=C=NCCCN(C)C.[C:33]([OH:36])(=O)[CH3:34]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:33](=[O:36])[CH3:34])(=[O:15])=[O:16])=[CH:10][C:9]=2[F:18])=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1ccc(Oc2ccc(S(N)(=O)=O)cc2F)c(O)c1
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NC(C)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of 4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzenesulfonamide (0.28 mmol; 90 mg) in anhydrous dichloromethane (1 mL), under argon were added EDAC (0.36 mmol; 69 mg), DMAP (0.31 mmol; 38 mg) and acetic acid (0.36 mmol; 0.02 mL). The reaction was stirred overnight at room temperature. Diluted with dichloromethane (3 mL), the mixture was washed with HCl (1N; 3 mL). The organic phase was dried over MgSO4, concentrated to yield the desired compound as a yellow foam (90 mg; 0.25 mmol; 89%), used as such in the following reaction.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:21]4[N:22]=[C:23]([C:25]5[CH:26]=[N+:27]([O-])[CH:28]=[CH:29][CH:30]=5)[N:24]=[C:20]4[N:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.C[CH2:33][N:34](CC)CC.[Si]([C:43]#[N:44])(C)(C)C>CC#N>[C:33]([C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]3[N:19]=[CH:18][CH:17]=[C:16]([C:8]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:15])[F:14])=[C:6]([O:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)[CH:7]=4)[N:21]3[N:22]=2)=[CH:26][N:27]=1)#[N:34].[C:43]([C:26]1[N:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:24]=[C:20]2[N:19]=[CH:18][CH:17]=[C:16]([C:8]3[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:15])[F:14])=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:7]=3)[N:21]2[N:22]=1)#[N:44]
Reactant: [O-][n+]1cccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)c1
Reactant: C[Si](C)(C)C#N
Reactant: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(-c2nc3nccc(-c4ccc(OC(F)F)c(OCC5CC5)c4)n3n2)cn1
Product: N#Cc1ncccc1-c1nc2nccc(-c3ccc(OC(F)F)c(OCC4CC4)c3)n2n1
Yield: 24 %
Yield: 72 %

Procedure:
In CH3CN, dissolved was 3-[7-{3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl}-[1,2,4]triazolo[1,5-a]pyri midine-2-yl]-pyridine-N-oxide (Compound 102) (0.5 g, 1.17 mmol). While stirring the solution, Et3N (0.2 g, 2.0 mmol) and TMSCN (0.47 g, 4.70 mmol) were slowly added dropwise thereto, and the resultant mixture was heated under reflux. The solvent was distilled under reduced pressure, and NaHCO3(aq) was added to the residue. The mixture was extracted three times with CH2Cl2, and the extract was washed twice with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to remove solvent. The mixture was purified via silica gel column chromatography (MC/EA, 2/1) to obtain the desired compound, 2-(2-cyano-pyridin-5-yl)-7-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine (Compound 123) (0.37 g, 72%) and 2-(6-cyano-pyridin-5-yl)-7-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine (Compound 124) (0.12 g, 24%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:32]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2Cl)n1
Temperature: 70 °C
Reaction time: 14 h
Yield: 52.4 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 1-[1-(4-Bromo-phenyl)-2-(2-chloro-phenyl)-1H-imidazol-4-yl]-ethanone (270 mg, 719 μmol), 3-methylsulfonylphenyl boronic acid (220 mg, 1.08 mmol), PdCl2dppf (55 mg, 10 mol %), K2CO3 (300 mg, 2.16 mmol), 1,2-dimethoxyethane (11 mL) and H2O (1 mL). The reaction solution was allowed to stir at 70° C. for 14 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NR4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 75% EtOAc to afford 170 mg (52% yield) of product. MS (ES): 451 [M+H]+, 473 [M+Na]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C@H:12]([CH3:26])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=1[CH2:45][C:46](O)=[O:47].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:24])([CH3:25])[CH3:23])[C@H:12]([CH3:26])[N:11]1[C:46](=[O:47])[CH2:45][C:38]1[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:37]=1[Cl:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)c(CC(=O)O)c1
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cl)c(CC(=O)N2[C@@H](CO[Si](C)(C)C(C)(C)C)Cc3c(CCC(C)(C)O)cccc3[C@@H]2C)c1

Procedure:
Dissolve 4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (0.36 g, 0.95 mol in dichloromethane (9.5 mL). Add diisopropylethylamine (499 μL, 2.86 mmol). Add 2-(2-chloro-5-methoxy-phenyl)acetic acid (229.5 mg, 1.14 mmol). Add O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (561 mg, 1.40 mmol) and stir at ambient temperature overnight. Dilute the reaction mixture with dichloromethane and wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a brown oil. Purify the residue by silica gel chromatography, eluting with acetone: hexanes (gradient, 0-20%) to give the title compound as an opaque oil (0.46 g, 0.82 mmol). MS (m/z): 560.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([NH2:26])=[S:25])=[CH:18][CH:17]=1>>[BrH:1].[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:24]2[S:25][CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=3[CH3:10])[N:26]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(CNC(N)=S)cc1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(NCc3ccc(C)cc3)n2)c(C)s1
Yield: 81 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (111 mg, 0.35 mmol) was allowed to react with 4-methylphenylmethylthiourea as described in Example 154, step (a) to give 125 mg (81% yield) of methyl 4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C18H18N2O2S2, 358.5 (M+H), found 359.1.
Reaction SMILES: CC1C=CN2C=C(CS)N=C2C=1.BrC[C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21](N(CC)C=O)=[N:20][C:19]=2[CH:28]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[O:22]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:28][C:19]=2[N:20]=[CH:21]1
Reactant: CCN(C=O)c1nc2cc(CBr)ccc2o1
Agent: Cc1ccn2cc(CS)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc2ocnc2c1
Reaction time: 2 h
Yield: 125.4 %

Procedure:
A mixture of 7-methylimidazo[1,2-a]pyridin-2-ylmethanethiol (1.5 g) and 5-bromomethyl-2-(N-ethylformamido)benzoxazole (2.9 g) in a solution of acetone (40 ml) and water (30 ml) was adjusted to pH 9-10 with saturated aqueous potassium carbonate solution under ice-cooling. The mixture was stirred for 2 hours at the same temperature and the isolated precipitate was collected by filtration to give 2-(N-ethylformamido)-5-(7-methylimidazo[1,2-a]pyridin-2-yl)methylthiomethyl]benzoxazole (1.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][O:18]1.[CH3:24][NH:25][CH3:26]>O1CCCC1>[CH3:24][N:25]([CH3:26])[CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CNC
Reactant: COc1ccccc1CCCCc1ccccc1OCC1CO1
Solvent: C1CCOC1
Product: COc1ccccc1CCCCc1ccccc1OCC(O)CN(C)C
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 260 mg of 2-{2-[4-(2-methoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran was treated with 2 ml of 50% by volume aqueous dimethylamine and then worked up. The resulting crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 250 mg (yield 84%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N+:20]([O-])=O)[CH:13]=2)=O)=[C:4]([N+:23]([O-])=O)[CH:3]=1>C(O)(=O)C.[Zn]>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:23][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([NH2:20])[CH:13]=1)=[CH:9]2
Reactant: COc1ccc(C(=O)Cc2cc(F)c(F)cc2[N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reaction time: 1 h

Procedure:
To a mixture of the product from Step C, 2-(4,5-difluoro-2-nitro-phenyl)-1-(4-methoxy-3-nitro-phenyl)-ethanone (4.00 g, 11.3 mmol) in glacial acetic acid (100 mL) was added in portions zinc dust (28 g, 325 mesh) at 0° C. Upon adding a few portions of zinc, the reaction mixture became a solid mass. The cooling bath was removed, and the remaining zinc was added in portions; the cooling bath was replaced, and stirring was continued for 1 hour at 0° C. and 1 hour at room temperature. The zinc metal was removed by filtration and the metal was washed with ethyl acetate. The organic solution was concentrated to dryness and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL). The layers were separated, the organic layer washed with brine, dried (magnesium sulfate), filtered, and concentrated to a tan solid. The solid was triturated with hexanes/ethyl acetate, 15/1, v/v and the insoluble portion collected by filtration (2.35 g), mp 210-211° C.