Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.S(O)(C(F)(F)F)(=O)=O.C(O[C@@H:39]1[O:61][C@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@H:40]1[O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C>CC(OC)(C)C.CC#N>[C:42]([O:41][C@@H:40]1[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[O:61][C@H:39]1[N:8]1[C:9]2[N:10]=[C:2]([Cl:1])[N:3]=[C:4]([NH2:11])[C:5]=2[N:6]=[CH:7]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: COC(C)(C)C
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 27.5 °C

Procedure:
Under an atmosphere of N2(g), 2-chloroadenine (A (9), 50 g, 294.9 mmol), MeCN (600 mL), and BSTFA (227.5 g, 883.8 mmol) were stirred and heated under reflux until the mixture turned mostly clear (about 1 h). TfOH (8.77 g, 58.5 mmol) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (C, 142.5 g, 282.5 mmol) were sequentially added into the mixture and were stirred at reflux for about 1 h. The mixture was cooled to 20-35° C. and diluted with MTBE (500 mL), and washed over a 0.5 to 1 h period with saturated NaHCO3 (750 mL). The organic phase was evaporated in vacuo at 40 to 50° C. to give 2′,3′,5′-tri-O-benzoyl-2-chloroadenosine (D): 1H NMR (300 MHz, CDCl3) δ 7.9-8.1 (m, 6H), 7.94 (s, 1H), 7.3-7.6 (m, 9H), 6.45 (d, J=2.7 Hz 1H), 6.15 (m, 2H), 5.30 (s, 2H), 4.90 (dd, J4′,5a=3.2 Hz, J5′a,5′b=12.0 Hz, 1H), 4.82 (m, 1H), 4.72 (dd, J4′,5a=4.1 Hz, J5′a,5′b=12.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.3, 165.5, 165.4, 156.4, 154.7, 151.1, 139.1, 134.1, 134.1, 133.8, 130.2, 130.1, 129.9, 129.4, 129.0, 128.8, 128.5, 119.1, 86.5, 81.3, 74.6, 71.7, 64.0.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCC(C)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 108.7 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid methyl ester (545 mg, 1.73 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide (830 mg, 19.8 mmol). The reaction mixture was stirred at 25° C. for 3 d. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (40 mL). This solution was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×40 mL). The combined organic extracts were then washed with a half-saturated sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid (565 mg, quant.) as a light brown solid: mp 73-76° C.; EI-HRMS m/e calcd for C19H24O3 (M) 300.1725, found 300.1724.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([OH:27])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([OH:27])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1cc(O)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Yield: 74.1 %

Procedure:
A solution of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-6-(methyloxy)-1H-indazol-4-ol (D4) (116 mg, 0.32 mmol) in ethanol (5 mL) and ethyl acetate (5 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and the product purified by silica gel chromatography eluting with 5-80% ethyl acetate in hexane to yield the title compound (E2) (65 mg).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:16]([NH:24][C:25](=[O:44])[C@H:26]([CH2:40][C:41](=[O:43])[NH2:42])[NH:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:15])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=C(C(OO)=[O:53])C=1>ClCCl>[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:5]([NH+:4]([O-:53])[CH2:3][C@@H:2]([OH:1])[C@@H:16]([NH:24][C:25](=[O:44])[C@H:26]([CH2:40][C:41](=[O:43])[NH2:42])[NH:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)N1CCC[C@H]1C(=O)NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Solvent: ClCCl
Product: CC(C)(C)N1CCC[C@H]1C(=O)[NH+]([O-])C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Yield: 66.7 %

Procedure:
A solution of 0.422 g of N -[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-N1 -tert.butyl-L-prolinamide and 142 mg of 3-chloroperbenzoic acid in 10 ml of dichloromethane was stirred at 20° C. for 1 hour. The solvent was then removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for theelution to give 289 mg of N1 -tert.butyl-N2 -[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]-butyl]L-prolinamide N2 -oxide as a white solid; MS: m/e 619 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O1[C:10]2([CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[O:27][CH3:28])[N:23]=[CH:22][NH:21][C:20]4=O)[CH2:12][CH2:11]2)[O:9]CC1.C(N(CC)CC)C.[Cl:37][C:38]1[C:39]([F:45])=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41]>C(#N)C>[Cl:37][C:38]1[C:39]([F:45])=[C:40]([NH:41][C:20]2[C:19]3[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][C:10](=[O:9])[CH2:15][CH2:14]4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2
Reactant: Nc1cccc(Cl)c1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3.25 ml phosphorus oxychloride are added dropwise to 6.50 g 6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-7-methoxy-3H-quinazolin-4-one in 65 ml acetonitrile under an argon atmosphere. Then the reaction mixture is heated to 40° C., combined dropwise with 5.00 ml triethylamine and refluxed for 2 h. After cooling to ambient temperature 1.40 ml triethylamine and 2.60 ml 3-chloro-2-fluoro-aniline, dissolved in 5 ml acetonitrile, are added and the reaction mixture is stirred overnight at 40° C. Then a further 0.70 ml of 3-chloro-2-fluoro-aniline dissolved in 2 ml acetonitrile are added dropwise and the reaction mixture is stirred for a further 10 h. After cooling to ambient temperature the precipitate formed is suction filtered, taken up in 1 N hydrochloric acid, combined with 6 N isopropanolic hydrochloric acid and stirred at ambient temperature until the ketal cleaving is complete. The precipitate formed is suction filtered and combined with methylene chloride and 1 N sodium hydroxide solution. The aqueous phase is separated off and extracted with methylene chloride, the combined extracts are evaporated down and the flask residue is brought to crystallisation with diisopropylether.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30]([NH:32][C:33]5[N:34]([C:42]6[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH2:49][CH2:50][OH:51])[CH:43]=6)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=5)=[O:31])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:61][S:62](Cl)(=[O:64])=[O:63].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:30](=[O:31])[NH:32][C:33]5[N:34]([C:42]6[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=6)[O:48][CH2:49][CH2:50][O:51][S:62]([CH3:61])(=[O:64])=[O:63])[N:35]=[C:36]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:37]=5)[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:1]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCO)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCOS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A yellow-orange solution of Intermediate 148f (137 mg, 0.198 mmol), DIPEA (0.10 mL, 0.60 mmol) and methanesulfonyl chloride (45 mg, 0.40 mmol) in DCM (5 mL) was stirred at 0° C. for 30 min, and at RT for 30 min. DIPEA (0.052 mL, 0.30 mmol) and MsCl (23 mg, 0.20 mmol) were added and the solution stirred at RT for 30 min. Water (2 mL) and sat. aq. NaHCO3 solution (2 mL) were added and the mixture shaken. The aqueous was extracted with DCM (5 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave the title compound as a yellow solid (100%). LCMS (Method 3): Rt 3.80 min, m/z 769 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(#N)C.O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH:9]1[CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[N:39][C:34]=3[CH2:33][O:32][C:31]3[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]2=3)[CH2:12][CH2:13][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: COC(=O)CC1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CC1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3-methoxycarbonylmethyl-piperazine (0.13 g, 0.5 mmol) in acetonitrile/water (8:2) (10 mL) was added K2CO3(0.2 g, 0.42 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.16 g, 0.42 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated, partitioned between EtOAc/H2O, and extracted with EtOAc (3×). The organics were combined, dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane to 100% ethyl acetate) to yield the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[CH:6]([CH3:8])[CH3:7])C.Cl.[NH2:21]O.C[O-].[Na+]>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]1[O:18][N:21]=[C:4]([OH:3])[C:5]=1[CH:6]([CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C(=O)c1ccc(F)cc1F)C(C)C
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)c1c(O)noc1-c1ccc(F)cc1F
Yield: 39.2 %

Procedure:
2-(2,4-Difluorobenzoyl)isovaleric acid ethyl ester (1.7 g), hydroxylamine hydrochloride (0.9 g) and sodium methoxide (28% methanol solution, 7.5 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(b) to obtain the title compound (0.59 g, 39%) as colorless crystals.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:20]1[CH2:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CN1CCN(C(=O)c2ccccc2)CC1
Reactant: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 31.6 %

Procedure:
To (4-benzoylpiperazin-1-yl)acetic acid ethyl ester (8.19 g) were added methanol (300 ml) and water (50 ml), and lithium hydroxide (1.34 g) was added thereto in an ice water bath, followed by stirring for 10 min. The reaction mixture was allowed to warm up to room temperature and stirred for 24 hr. After addition of 1N hydrochloric acid (55.9 ml), the reaction mixture was concentrated under reduced pressure, and ethanol (200 ml) was added to the resultant residue. Precipitated insoluble matter was filtered through celite. The filtrate was concentrated to provide a crude product of (4-benzoylpiperazin-1-yl)acetic acid as a white solid (8.6 g). To (4-benzoylpiperazin-1-yl)acetic acid (2 g) was added N,N-dimethylformamide (80 ml) under a nitrogen atmosphere at room temperature, and azetidine hydrochloride (1.51 g), triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added thereto in this order, followed by stirring at room temperature for 66 hr. Liquid-liquid separation was carried out after addition of ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, the resultant residue was suspended in diethyl ether (10 ml). The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (731.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17](Br)[C:18]#[CH:19].O>C1(C)C=CC=CC=1>[CH2:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CCNc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A solution of 4-aminobenzonitrile, 5 g (0.042 mol), triethylamine, 8.55 g (0.085 mol), and an 80% by weight solution of propargyl bromide in toluene, 12.6 g (0.085 mol), in toluene is refluxed overnight. The solution is cooled to room temperature and poured into water. The organic layer is separated, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is purified by chromatography over silica gel to give 4-(2-propynylamino)benzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[N:17]=[C:16]([C:19]4[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[NH:15][C:14]=3[C:13]3[C:8](=[CH:9][C:10]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:11][CH:12]=3)[C:6]=2[CH:7]=1.[CH:33]1([C:36]#[CH:37])[CH2:35][CH2:34]1.C(NC(C)C)(C)C.[NH4+].[OH-]>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.[Cu](I)I.C(OCC)(=O)C.CN(C=O)C>[CH:33]1([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]3[C:18]4[N:17]=[C:16]([C:19]5[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][C:20]=5[C:21]#[N:22])[NH:15][C:14]=4[C:13]4[C:8](=[CH:9][C:10]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:11][CH:12]=4)[C:6]=3[CH:7]=2)[CH2:35][CH2:34]1
Reactant: CC(C)(O)c1ccc2c(c1)c1cc(Br)ccc1c1nc(-c3c(C#N)cccc3C#N)[nH]c21
Reactant: C#CC1CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc2c(c1)c1cc(C#CC3CC3)ccc1c1nc(-c3c(C#N)cccc3C#N)[nH]c21
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A round bottomed flask containing 2-[6-bromo-9-(1-hydroxy-1-methylethyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile from Example 87 (1.26 g, 2.62 mmol), Pd(PPh3)4 (190 mg, 0.27 mmol) and copper iodide (100 mg, 0.52 mmol) was purged with nitrogen for 15 minutes, followed by addition of DMF (50 mL), cyclopropyl acetylene (1.4 mL, 21 mmol) and di-isopropylamine (560 μL, 4 mmol). The resulting mixture was heated at 60-65° C. for 3.5 h, cooled to room temperature and then poured into a mixture of NH4OH and ethyl acetate and stirred for 1 h. The aqueous phase was extracted with ethyl acetate, the organic layer washed once with water, once with brine, dried over Na2SO4, filtered and concentrated. The material obtained after purification by flash chromatography on silica (30-100% ethyl acetate in toluene) was swished in toluene for 2 h and then filtered to afford 2-[6-(cyclopropylethynyl)-9-(1-hydroxy-1-methylethyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile as a yellow solid (350 mg). The mother liquor was combined with the mixed fractions and re-purified by flash chromatography on silica (3-40% acetonitrile in toluene) to afford 286 mg the bis-nitrile (total yield 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16]>C1COCC1>[CH3:14][N:15]([CH3:16])[S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrobenzenesulfonyl chloride (22.8 mmol, 5.05 g) was dissolved in dry THF (50 mL). Dimethylamine in THF (2M, 34 mL) was added and the mixture was refluxed for 2 hours. Upon cooling, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with water (3×50 mL) and dried over MgSO4. Evaporation of the solvent afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([C:17]3[C:18]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([OH:24])=O)[NH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:42]([C:41]1[CH:40]=[CH:39][C:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:22]([C:21]3[C:20]([CH3:26])=[CH:19][C:18]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:17]([C:15]4[NH:16][C:10]5[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][C:11]=5[N:14]=4)[CH:25]=3)=[O:24])[CH2:33][CH2:34]2)=[CH:45][CH:44]=1)#[N:43]
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 8 h
Yield: 126.9 %

Procedure:
To a solution of 5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoic acid (compound 406.1, 1.00 g, 1.22 mmol, 1.00 equiv, 50%) in N,N-dimethylformamide (5 mL) were added 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5, 270 mg, 1.21 mmol, 1.00 equiv), EDC.HCl (460 mg, 2.40 mmol, 2.00 equiv), and 4-dimethylaminopyridine (296 mg, 2.42 mmol, 2.00 equiv). The resulting mixture was stiffed at 25° C. overnight. The mixture was then diluted with 30 mL of ethyl acetate, washed with 3×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 890 mg (63%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)=[O:4].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N(CC)CCCl)C>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:20]=[CH:19][CH:18]=[C:7]([O:8][C:9]2[C:10]([C:11](=[O:13])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=3)=[CH:14][CH:15]=[CH:16][N:17]=2)[CH:6]=1
Reactant: COC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: CCN(CC)CCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)c1

Procedure:
To a stirred solution of 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid (0.400 grams, 1.463 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.266 grams, 1.61 mmole), and 1-hydroxybenzotriazole hydrate (0.237 grams, 1.755 mmole) in dry dimethylformamide (20 ml) was added 2-diethylaminoethyl chloride hydrochloride (0.365 grams, 1.90 mmole) and stirred over night. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give a white foam. (0.360 g); MS (m/e) 420 (M++1); 1H NMR (CDCl3) d 1.50 (6H, s), 3.90 (3H, s), 4.70 (2H, d, J=5.60 Hz), 7.20-8.65 (12H, m).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16](O)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:24]=3[OH:23])=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NCc1ccc(O)cc1O
Reactant: COc1cc(O)c(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COc1cc(O)c(C(=O)NCc2ccc(O)cc2O)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.14 g of the target compound is obtained as solid of a light color in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2-hydroxy-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 2,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([N:22](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][NH2:22])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: OCc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of [2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-methanol (110 mg, 0.43 mmol), diisopropylethylamine (0.10 mL, 0.52 mmol), and CH2Cl2 (5 mL) was added methanesulfonyl chloride (37 μL, 0.47 mmol). After 1 h, the resulting solution was concentrated. The residue was re-dissolved in 7N NH3 in MeOH (10 mL) and heated to 70° C. in a sealed tube. After 1 h, the resulting solution was cooled, concentrated, and the residue was used crude (110 mg, 100%). MS (ESI): mass calcd. for C12H10F3N3, 253.0; m/z found, 254.1 [M+H]+.