Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C(Cl)=S)C1C=CC=CC=1>ClCCCl.CN(C)C1C=CN=CC=1>[C:1]([O:9][C@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: S=C(Cl)Oc1ccccc1
Solvent: ClCCCl
Product: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)C[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of 1-(3,5-di-O-benzoyl-β-L-arabinofuranosyl)uracil 12 (5.2 g, 11.4 mmoL) in anhydrous 1,2-dichloroethane (120 mL) were added phenoxythiocarbonyl chloride (4.7 mL, 34.3 mL) and 4-(dimethylamino)pyridine (DMAP, 12.5 g, 102.6 mmol.). The resulting solution was stirred at room temperature under argon atmosphere for 1 h and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and the organic solution was successively washed with an ice-cold 0.2 N hydrochloric acid solution (3×200 mL) and water (2×200 mL), dried over Na2SO4 then evaporated under reduced pressure. The crude material was co-evaporated several times with anhydrous dioxane and dissolved in this solvent (110 mL). To the resulting solution were added under argon tris-(trimethylsilyl)silane hydride (4.2 mL, 13.7 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.6 g, 3.76 mmol). The reaction mixture was heated and stirred at 100° C. for 1 h under argon, then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-5%)] to give 13 (2.78 g, 56%) which was crystallized from EtOH: mp=223-225° C.; 1H-NMR (DMSO-d6): δ 11.4 (br s, 1H, NH), 8.0-7.5 (m, 11H, 2 C6H5CO, H-6), 6.28 (t, 1H, H-1′, J=7 Hz), 5.5 (m, 2H, H-1′ and H-5), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 2H, H-2′ and H-2″); MS: FAB>0 (matrix GT) m/z 437 (M+H)+, 3325 (S)+; FAB<0 (matrix GT) m/z 435 (M−H)−, 111 (B)−; Anal. Calcd for C23H20N2O7: C, 63.30; H, 4.62; N, 6.42. Found: C, 62.98; H. 4.79; N, 6.40.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:12]=2[C:13]#[N:14])=[CH:6][C:5]=1[C:21]([F:24])([F:23])[F:22].[CH2:25]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:25])=[CH:15][C:12]=2[C:13]#[N:14])=[CH:6][C:5]=1[C:21]([F:24])([F:23])[F:22]
Reactant: C1CCOC1
Reactant: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a solution of NaH (0.798 g, 19.96 mmol) in dry THF (15 mL) was added methyltriphenylphosphonium bromide (7.13 g, 19.96 mmol). The mixture was stirred at room temperature for 0.5 h. Then 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-formylbenzonitrile (5.0 g, 15.35 mmol) was added. Stirring continued for 1.5 h, and the mixture was quenched by ice water. THF was removed by evaporation; the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound (1.8 g, 5.56 mmol, 36.2% yield).
Reaction SMILES: [CH3:1][C:2]([O:16][Si](C)(C)C)([CH3:15])[C:3]#[C:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:16][C:2]([CH3:15])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1ccc(C#N)cc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
To a stirred solution of 4-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (1.7 g, 5.00 mmol) in DCM (15 mL) was added PTSA (1.70 g, 8.90 mmol) at RT and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.20 g) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])(O)O>>[F:12][C:8]1[C:7]([OH:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])=[N:3]2
Reactant: Oc1ccc2nc(Cl)ccc2c1F
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Product: Cc1cc(C(=O)O)ccc1-c1ccc2c(F)c(O)ccc2n1

Procedure:
Followed the procedure described for Example 70, starting from 2-chloro-5-fluoroquinolin-6-ol (Intermediate 16) and 4-borono-3-methylbenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.03 (b, 1H), 10.47 (b, 1H), 8.43 (d, 1H), 7.93 (s, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.52 (t, 1H), 2.43 (s, 3H). MS (ESI): m/z=296.38 [M−1]−.
Reaction SMILES: [F:1][C:2]1[C:3]([O:32]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:6][C:5]2([CH3:31])[CH3:30].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:3]([OH:32])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:26])[F:27])[CH2:6][C:5]2([CH3:30])[CH3:31]
Reactant: COc1c(F)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(c(O)c1F)C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
59.7 mg (0.128 mmol) of (rac.) 5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one is mixed at 0° C. with 1.3 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for one hour at 0 to 5° C. At -10C, saturated sodium bicarbonate solution is now carefully added in drops. After 10 minutes of vigorous stirring at room temperature, the batch is extracted three times with methyl tert-butyl ether. The organic phases are dried, and after the solvent is spun off, the residue is chromatographed on a Flashmaster. 46.5 mg (80.3%) of the desired compound is isolated.
Reaction SMILES: Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:70]=[C:69]([N+:71]([O-])=O)[CH:68]=[CH:67][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:66])[C:54]([O:56][CH2:57][CH2:58][CH2:59][N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1>>[F:43][C:44]1[CH:70]=[C:69]([NH2:71])[CH:68]=[CH:67][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:66])[C:54]([O:56][CH2:57][CH2:58][CH2:59][N:60]3[CH2:61][CH2:62][O:63][CH2:64][CH2:65]3)=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1
Reactant: Cc1c(OCCCN2CCOCC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCCN2CCOCC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 96.9 %

Procedure:
Following a procedure similar to that for the synthesis of Compound C of Example 36, 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(3-morpholinopropoxy)pyrrolo[2,1-f][1,2,4]triazine (31 mg, 0.072 mmol) was converted to the title compound (28 mg, 95%). MS(ESI+) m/z 402.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.Cl[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[N:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:11][CH:12]3[CH:16]([CH2:15][N:14]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([C:31]([F:33])([F:34])[F:32])[N:25]=4)[CH2:13]3)[CH2:17]2)=[O:9])[CH:7]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Reactant: Cc1cc(Cl)nc(C(F)(F)F)n1
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 21 and 4-chloro-6-methyl-2-trifluoromethyl-pyrimidine. MS (ESI): mass calculated for C21H19F4N7O, 461.42; m/z found 462.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.04-7.87 (m, 1H), 7.81-7.63 (m, 1H), 7.29-7.18 (m, 1H), 7.17-7.08 (m, 1H), 6.31-6.03 (m, 1H), 4.13-2.84 (m, 10H), 2.44 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[Si:15]([O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
To a solution of 1H-indazol-5-ol (400 mg, 2.98 mmol) in DMF (10 mL) was added TBDMSCl (537 mg, 3.58 mmol) and imidazole (405 mg, 5.96 mmol) at 0° C. and the resulting mixture was stirred at 25° C. for 16 h. The reaction was quenched by addition of water and the product extracted with ethyl acetate. The organic phase was washed with brine, then dried over Na2SO4, and concentrated under reduced pressure to give 5-((tert-butyldimethylsilyl)oxy)-1H-indazole (500 mg, yield 68%) as a brown solid, which was used in the next step without further purification. LCMS (m/z): 249.1 [M+H]+
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([O:12][CH:13]1[CH2:31][CH:30]2[N:15]([C:16](=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]3[C:27]([C:33](O)=[O:34])([NH:28][C:29]2=[O:32])[CH2:26]3)[CH2:14]1)=[O:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:49]1([S:52]([NH2:55])(=[O:54])=[O:53])[CH2:51][CH2:50]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[C:10]([O:12][CH:13]1[CH2:31][CH:30]2[N:15]([C:16](=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]3[C:27]([C:33]([NH:55][S:52]([CH:49]4[CH2:51][CH2:50]4)(=[O:54])=[O:53])=[O:34])([NH:28][C:29]2=[O:32])[CH2:26]3)[CH2:14]1)=[O:11]
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C1NC2(C(=O)O)CC2C=CCCCCCCC(=O)N2CC(OC(=O)N3Cc4ccccc4C3)CC12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC2(C(=O)NS(=O)(=O)C3CC3)CC2C=CCCCCCCC(=O)N2CC(OC(=O)N3Cc4ccccc4C3)CC12
Temperature: 25 °C

Procedure:
The mixture of carboxylic acid 18 (30 mg, 0.06 mmole) and CDI (20 mg, 2 eq) in dry THF (3 mL) was stirred at reflux for 2 h30 under nitrogen. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled at room temperature and cyclopropylsulfonamide (15 mg, 2 eq) and DBU (18 mg, 2 eq) were added. The reaction mixture was stirred at 50° C. until completion as indicated by LC-MS. The RM was then concentrated, redissolved in DCM and extracted with HCl 1M then brine, dried and concentrated. Purification by flash chromatography on silica gel afforded the desired product 19. m/z=599 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1([OH:18])[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:22]>C1COCC1>[CH2:1]([C:8]1([O:18][CH3:22])[CH2:17][CH2:16][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(Cc2ccccc2)CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(Cc2ccccc2)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of Example 11A (8.08 g, 32.5 mmol) in THF (150 mL) at room temperature was treated with 60% NaH in mineral oil (3.2 g, 80 mmol), stirred for 1 hour, treated with iodomethane (5 mL, 80 mmol), stirred overnight, quenched with saturated NH4Cl, and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (CI) m/e 280.2 (M+18)+.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19]CC)=[O:18])C.[C:22]1(C)C=CC(S(O)(=O)=O)=C[CH:23]=1.[OH-].[Na+].Cl>>[CH2:22]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[C:4](=[O:3])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]1)[CH3:23]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Temperature: 180 °C
Yield: 4856.1 %

Procedure:
A mixture of 5 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-carboxylate and 0.06 g of p-toluene-sulfonic acid was heated at 180°C for 3 hours and cooled. To the product was added 50 ml of a 5% aqueous sodium hydroxide solution. The resulting mixture was heated at 90°-100°C for 30 minutes, the acidified by the addition of dilute hydrochloric acid and cooled. The precipitate was collected by filtration, washed with water and dried. There was obtained 4.42 g of 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylic acid, m.p. 318°C (decomposition).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][OH:22])[O:18][C:17]3=[O:23])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)#[N:2]>[Pd]>[C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][OH:22])[O:18][C:17]3=[O:23])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Agent: [Pd]
Product: N#CCC1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
The suspension of (R)-{3-[4-(4-cyanomethylidenepiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-alcohol (0.11 mmol), 10% palladium on carbon (0.1 g) tetrahydrofuran was stirred under atmospheric hydrogen pressure at 30° C. for overnight.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:35])[C:16]=2[N:17]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OCC3C=CC=CC=3)[CH2:19][CH2:18]2)=[O:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.C1CC=CCC=1>[Pd].C(O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:35])[C:16]=2[N:17]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19][CH2:18]2)=[O:10])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Cn1ncc(NC(=O)c2nc(Cl)ncc2N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cn1ncc(NC(=O)c2ncncc2N)c1N1CCC[C@@H](N)CC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
In a 40 mL sealed vial was added (R)-benzyl 1-(4-(5-amino-2-chloropyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate (140 mg, 0.28 mmol), 1,4-cyclohexadiene (0.16 mL, 1.68 mmol) and ethanol (12 mL). 10% Pd/C (30 mg, 0.028 mmol) was added and the reaction vial was vacuum purged with nitrogen three times. The reaction mixture was then stirred at 95° C. under nitrogen for 2 h. LCMS indicated de-chlorinated product as the malor product. After cooling down to room temperature, the reaction mixture was filtered through Celite and rinsed thoroughly with methanol. The solvent was distilled off under reduced pressure to give the crude product which was purified via reverse phase HPLC to afford 326. 1H NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 8.46 (s, 1H), 7.51 (s, 1H), 6.88 (s, 3H), 3.65 (s, 4H), 3.19-2.89 (m, 9H), 1.93-1.69 (m, 4H), 1.69-1.41 (m, 4H). MS (ESI) m/z: 331.2 [M+H+].
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=O>CO.C1CCCCC1>[C-:1]1([C:15]([C-:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)([CH3:17])[CH2:14][CH2:13][C:12]([O:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:11].[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:11]
Reactant: COC(=O)CCC(C)=O
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1CCCCC1
Solvent: CO
Product: COC(=O)CCC(C)([c-]1cccc1)[c-]1cccc1

Procedure:
REACTING FERROCENE AND METHYL LEVULINATE IN THE PRESENCE OF AN ACID SUCH AS POLYPHOSPHORIC ACID AND A METHANOL-CYCLOHEXANE SOLVENT AT A TEMPERATURE OF FROM 76° TO 78°C to produce methyl 4, 4-diferrocenylpentanoate; and
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Cl)c2F)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)c(C(Cl)=Nc2ccnc(Cl)c2F)c(Cl)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-benzamide (1.2 g, 3.4 mmol) and thionyl chloride (12.5 mL) was heated under reflux for 18 hours then cooled to ambient temperature. The reaction mixture was diluted with toluene (10 mL) and concentrated to dryness under reduced pressure to afford the title compound as a white solid (1.23 g, 97% yield). 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=5.1 Hz, 1H), 7.75 (s, 2H), 6.97 (t, J=5.1 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cc(F)ccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(F)ccc1Cl
Yield: 10 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-5-fluorophenylboronic acid (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-fluoro-biphenyl-2-carboxylic acid (12 mg, 10%). 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.55 (d, J=1.7 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.29 (dd, J=8.1, 1.9 Hz, 1H), 8.09 (dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.6, 5.7 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[C:13]([NH:19][C:20]3[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:25])=[CH:22][CH:21]=3)=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)C.Cl.[NH+]1C=CC=CC=1>O>[O:3]=[C:4]1[CH:9]=[C:8]([C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[C:13]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:25])=[CH:34][CH:35]=3)=[N:12][CH:11]=2)[CH:7]=[CH:6][NH:5]1
Reactant: CCOc1cc(-c2cnc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3nccn23)ccn1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc(Nc2ncc(-c3cc[nH]c(=O)c3)n3ccnc23)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-[5-(2-ethoxypyridin-4-yl)imidazo[1,2-a]pyrazin-8-ylamino]-N-pyridin-3-ylmethyl benzamide (82 mg, 0.18 mmol) and pyridinium hydrochloride (101 mg, 0.88 mmol) in water (0.5 mL) is heated at 150° C. for 20 minutes in a sealed tube. After this time the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 90:10 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a solid. HPLC (254 nm): Rt 1.83 min (99.1%); m/z (APCI) 438 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])C.Cl.[NH2:21][OH:22].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[O:22][N:21]=1
Reactant: CCOC(=O)C(Br)=C(Br)c1ccccc1C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(-c2ccccc2C(F)(F)F)on1
Yield: 74.5 %

Procedure:
α,β-Dibromo-2-trifluoromethylcinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and sodium hydroxide (9.1 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (7.6 g, 76%) as colorless crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26](Cl)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Reactant: CN1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(N3CCN(C)CC3)c21
Yield: 47 %

Procedure:
The title compound (47% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 1-methylpiperazine according to the procedure described for Example 14. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (br s, 1H, NH), 11.83 (br s, 1H, NH), 10.56 (v br s, 1H), 8.45 (v br s, 1H), 8.38 (s, 1H, H-vinyl), 7.09 (s, 1H), 6.87 (s, 1H), 3.4-3.6 (m, 10H, 5×CH2), 2.85 (m, 4H, 2×CH2), 2.4-2.6 (m, 6H, 3×CH2), 2.49 (under DMSO, 3H, CH3), 2.31 (s, 3H, CH3). MS 481.3 [M++1].
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([C:14]#[N:15])=[C:10]([C:12]#[N:13])[N:11]=1)[CH2:4][CH2:5][CH3:6].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:3]([C:7]1[N:11]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:10]([C:12]#[N:13])=[C:9]([C:14]#[N:15])[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(C#N)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(C#N)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
1.25 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 5 g of 2-butylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 1) in 50 ml of N,N-dimethylformamide, and the resulting mixture was stirred for 15 minutes. 10 g of trityl chloride were then added, and the reaction mixture was stirred at 50° C. for 6 hours. At the end of this time, it was mixed with ethyl acetate and water, and the product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent, to give 9.83 g of the title compound as a syrup, which solidified on being allowed to stand. The solid melted at 144°-147° C. (with decomposition and coloration at 94°-98° C.).