Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]1([CH2:22][CH2:23][CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCCCC>CN(C1C=CN=CC=1)C.CCO.C1COCC1>[CH2:1]([O:27][C:26](=[O:28])[CH:25]=[CH:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C=CCCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
The reagents DCC (33 mM) and DMAP (30 mM) were added to a solution of 5-phenylpent-2-enoic acid (5.3 g, 30 mM) in EtOH (50 mL) and THF (20 mL), which was cooled to 0° C. The resulting mixture was stirred for 30 min at 0° C., then allowed to react for 15 h at room temperature. The suspension was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with 1 M HCl (3×30 mL), H2O (10 mL), saturated NaHCO3 (3×30 mL), H2O (10 mL), saturated NaCl (20 mL), dried over MgSO4, and concentrated. Chromatography on a silica gel column using 1:2 EtOAc:hexane as the eluent afforded 5-phenyl-pent-2-enoic acid ethyl ester (3.75 g, yield=61%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([Sn]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(CCCC)CCCC)CCC>CN(C=O)C.CCOCC>[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2cccs2)ccc1O
Temperature: 80 °C
Yield: 65.5 %

Procedure:
The synthesis of this compound is depicted schematically in FIG. 13. To a mixture of 5-bromosalicylaldehyde (2.847 g, 14.16 mmol) and Cl2Pd(PPh3)2 (0.497 g, 0.708 mmol, 0.05 equiv) was added tributylstannyl thiophene (6.75 mL, 21.24 mmol, 1.5 equiv) in 25 mL of DMF. The reaction mixture was heated at 80° C. 16 h, over which time the reaction color changed from light yellow to dark red. The reaction was cooled, diluted with Et2O and washed with dilute NH4Cl (4×150 mL). The organic layer was collected and filtered through a short silica pad to yield a yellow filtrate. The solvent was removed under reduced pressure to afford a gummy yellow solid, which was transferred to a frit and washed with hexanes. The yellow solid was dried in vacuo to afford 1.895 g (9.28 mmol, 66%) of a yellow powder (mp 102-103° C.). 1H NMR (CDCl3) δ11.01 (s, 1H), 9.96 (s, 1H), 7.80-7.76 (m, 2H), 7.29-7.24 (m, 2H), 7.11-7.07 (dd, 1H), 7.05-7.02 (dd, 1H). 13C NMR (CDCl3) δ196.5, 161.1, 142.7, 134.7, 130.8, 128.3, 127.1, 124.8, 123.0, 120.8, 118.4. MS m/z (204 (M+). HRMS (FAB) found m/z 205.0324 (M+H+); calcd for C11H9O2S m/z 205.0323 (M+H+).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]#[N:26])=[CH:19][C:18]=3[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:13][C:12]=2[CH:31]([CH3:33])[CH3:32])=[CH:7][C:6]=1[CH2:34][CH:35]([CH3:37])[CH3:36])#[N:2].[ClH:38]>CCO>[ClH:38].[ClH:38].[NH2:2][CH2:1][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][NH2:26])=[CH:19][C:18]=3[CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:13][C:12]=2[CH:31]([CH3:33])[CH3:32])=[CH:7][C:6]=1[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Cc1cc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2C(C)C)ccc1OCC#N
Agent: Cl
Solvent: CCO
Product: CC(C)Cc1cc(-c2ccc(-c3ccc(CCCN)cc3CC(C)C)cc2C(C)C)ccc1OCCN
Reaction time: 8 h
Yield: 91 %

Procedure:
3-[4″-(cyanomethoxy)-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl]propanenitrile (8f) (19.0 mg, 0.038 mmol) was dissolved in 5 ml of EtOH containing 10% Pd/C (15 mg) and 0.1 ml HCl (conc.). The solution was stirred overnight under 20 psi of H2. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to yield 20 mg of a white solid (91%): 1H NMR (500 MHz, CD3OD) δ 0.75 (d, J=6.6 Hz, 6H), 0.93 (d, J=6.9 Hz, 6H), 1.14 (d, J=6.9, 6H), 1.68 (m, 2H), 1.96 (m, 1H), 1.99 (m, 1H), 2.54 (d, J=6.6 Hz, 2H), 2.62 (d, J=6.9 Hz, 2H), 2.76 (t, J=7.4, 2H), 2.96 (t, J=6.8 Hz, 2H), 3.11 (m, 1H), 3.41 (t, J=4.5 Hz, 2H), 4.29 (t, J=5.0 Hz, 2H), 7.13 (m, 9H); 13C NMR (125 MHz, CD3OD) δ 22.85, 22.96, 24.61, 30.15, 30.53, 30.54, 30.81, 33.34, 40.12, 40.53, 40.70, 43.42, 66.06, 112.90, 126.84, 127.50, 127.67, 129.06, 130.75, 131.25, 131.29, 131.33, 133.29, 136.26, 140.46, 140.49, 140.59, 141.95, 142.56, 147.13, 156.52; HRMS (FAB, M+H) Calcd for C34H49N2O: 501.3845. Found 501.3845.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C(=O)=O.CC(C)=O.[H-].[Na+].[CH3:21][N:22]([CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>O1CCCC1>[CH3:21][N:22]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35](/[CH:36]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[CH:38][CH:39]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc(OCCN(C)c2ccccn2)cc1
Reaction time: 0.17 h

Procedure:
A solution of trimethyl phosphonoacetate (5.5 mL) in dry tetrahydrofuran (25 mL) was added slowly to a cooled (cardice-acetone bath) suspension of sodium hydride (60% dispersion in oil, 1.34 g) in tetrahydrofuran (100 mL) under a nitrogen atmosphere such that the temperature of the reaction mixture remained between 0° C. and 10° C. during the addition. The resultant slurry was then cooled in an ice bath and stirred for 10 minutes prior to the addition of a solution of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (8.3 g) (Eur. Patent. Appl., Publication No. 0306228) in tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 20 hrs, then quenched with brine (10 mL) and concentrated in vacuo. The residue was suspended in brine (500 mL) and extracted with dichloromethane (3×300 mL), and the combined organic layers washed with water (1 L) and brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, mp 93°-5° C. (dichloromethane-hexane).
Reaction SMILES: Br[C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][Br:7].C(NC1C=C(OC)C=CC=1Cl)(=O)C.[C:22]([NH:25][C:26]1[CH:31]=[C:30]([O:32]C)[CH:29]=[CH:28][C:27]=1[Br:34])(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[C:27]([Br:34])=[CH:28][C:29]([C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][Br:7])=[C:30]([OH:32])[CH:31]=1)(=[O:24])[CH3:23]
Reactant: COc1ccc(Br)c(NC(C)=O)c1
Reactant: O=C(Br)CCCCBr
Agent: COc1ccc(Cl)c(NC(C)=O)c1
Product: CC(=O)Nc1cc(O)c(C(=O)CCCCBr)cc1Br

Procedure:
Proceeding as in Example 4, Step (a), but replacing 1,5-dichlcoro-pentan-1-one with 1,5-dibromopentan-1-one and N-acetyl-2-chloro-5-methoxyaniline with N-acetyl-2-bromo-5-methoxyaniline, gave 1-(4-acetylamino-5-bromo-2-hydroxyphenyl)-5-bromopentan-1-one.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](B(O)O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:22]=[C:23](I)[CH:24]=[CH:25][CH:26]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[Br:20][C:21]1[CH:22]=[C:23]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(-c2ccccc2)c2ccccc12
Reactant: Brc1cccc(I)c1
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: Cc1ccccc1
Solvent: COCCOC
Product: Brc1cccc(-c2ccc(-c3ccccc3)c3ccccc23)c1
Yield: 61.9 %

Procedure:
Under the atmosphere of argon, 11.6 g of 1-phenylnaphthalene-4-boronic acid and 14.5 g of 3-bromoiodobenzene were dissolved into 160 ml of toluene and 30 ml of DME, and 1.79 g of tetrakis(triphenylphosphine)palladium was added to the obtained solution. After 90 ml of a 2 M aqueous solution of sodium carbonate was added, the resultant mixture was heated under the refluxing condition for 8 hours. After the obtained mixture was left standing for one night, the mixture was subjected to extraction with toluene. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was removed using an evaporator. The residue was purified in accordance with the silica gel column chromatography (the developing solvent: hexane/toluene=5/1), and 10.4 g of 1-(3-bromophenyl)-4-phenylnaphthalene was obtained as white crystals (the yield: 62%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:25][O-:26].[Na+]>CO>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][O:26][CH3:25])[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CCl)ccn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A mixture of 2-amino-6-[2-(7-chloromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.4 g), and sodium methoxide (0.13 g) in methanol (10 ml) was stirred for 3 hours at 40°-50° C. and the solvent was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and tetrahydrofuran and the mixture was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by silica gel column chromatography eluting with a solution of chloroform and methanol (9:V/V). The fraction containing object compound were concentrated to give 2-amino-6-[2-(7-methoxymethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.22 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][O:45]CC4C=CC=CC=4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][CH2:44][OH:45])=[CH:39][CH:40]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCOCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCO)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 16 h

Procedure:
To a 0.5 L round bottom flask add [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-(3-benzyloxypropoxy)phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (10.34 mmol) and ethyl acetate (80 mL). To this solution add 5% Pd/C pre wet with ethyl acetate (20 mL). While stiffing, vacuum purge the mixture with hydrogen (3×) then stir under hydrogen for 16 hours. Filter through diatomaceous earth and rinse with ethyl acetate (100 mL). Concentrate the filtrate under reduced pressure to give the title compound in sufficient purity to use in the next step (6.5 g): mass spectrum (m/z): 626.4 (M+1).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][O:7][C:8]2([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([S:43]([N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]2[CH2:52][O:53][CH2:54]C(O)=O)(=[O:45])=[O:44])=[C:38]([CH3:58])[CH:37]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1([CH2:5][CH2:6][O:7][C:8]2([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[CH2:54][O:53][CH2:52][C@@H:47]3[CH2:48][CH2:49][CH2:50][CH2:51][N:46]3[S:43]([C:39]3[C:40]([CH3:42])=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=3[CH3:58])(=[O:45])=[O:44])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCC2)(c2cccnc2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCC3)(c3cccnc3)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
After the BOC deprotection of tert-butyl 4-(2-(azetidin-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate [amine E] (0.15 g, 1.2 eq.) in the presence of TFA (10-13 eq.) in methylene chloride (see e.g. stage (iii)/amine H), the amine was added to a cooled (0° C.) solution comprising (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (1 eq.), EDCl (1.5 eq.), HOBT (1 eq.) and DIPEA (3 eq.) in methylene chloride (10 ml). When the addition was complete, the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with methylene chloride and washed with aqueous ammonium chloride solution and aqueous sodium bicarbonate solution. After concentration, the crude product was purified by means of column chromatography (Alox). Yield: 39%. MS, Rt=2.7 min, m/z=615.4 [MH]+
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][N:9]3[C:10]=2[C:2]=1[C:3]1[C:4](=[N:16]O)[CH2:5][CH2:6][CH2:7][C:8]=13.[OH2:18]>>[CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][N:9]3[C:10]=2[C:2]=1[C:3]1[C:4](=[O:18])[NH:16][CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: ON=C1CCCc2c1c1cccc3c1n2CC3
Reactant: O
Product: O=C1NCCCc2c1c1cccc3c1n2CC3
Reaction time: 1 h

Procedure:
4,5,8,9-Tetrahydropyrrolo[3,2,1-jk]carbazol-10(7H)-one oxime (244 mg) was added to polyphosphoric acid (20 ml) at 120°, and the mixture was stirred at 120° for 1 h. After cooling, the mixture was poured into water (150 ml) and extracted with dichloromethane: ethanol (10:1; 4×100 ml). The combined, dried organic extracts were evaporated under reduced pressure to give a solid (150 mg) which was purified by FCC eluting with System A (100:10:1) to give the title compound (92 mg), t.l.c. (System A, 100:10:1) Rf 0.47.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=2)[CH2:9][CH2:8]1.B(Br)(Br)Br>ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:9][CH2:8]1
Reactant: COc1cccc(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1cccc(O)c1
Yield: 137.5 %

Procedure:
The product of Example 10 (0.15 g) was dissolved in dichloromethane (10 ml) and a solution of 1.0M BBr3 in dichloromethane (4 ml) added. After 16 hours at room temperature the solvent was removed by evaporation, methanol was added and the solution concentrated. The residue was dissolved in 2M aqueous HCl solution, concentrated to dryness and the residue triturated under ether to give the titled product as a solid (0.1 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:19]1([NH:25][C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:19]1([NH:25][C:26]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: O=C(Nc1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2CCC(C(=O)Nc3ccccc3)CC2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 100 mg (0.32 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 230 mg (0.96 mmoles) of piperidine-4-carboxylic acid phenylamide in 5 ml of DMF, 130 mg (0.96 mmoles) of K2CO3 is added at ambient temperature. The reaction mixture is stirred for 18 hours at ambient temperature. The reaction mixture is quenched with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 130 mg of disired 1-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-piperidine-4-carboxylic acid phenylamide in 95% yield.
Reaction SMILES: [Na].Cl[C:3]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH3:16][OH:17]>>[CH3:16][O:17][C:3]1[C:12]2[C:7](=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: CO
Agent: [Na]
Product: COc1nccc2c([N+](=O)[O-])cccc12

Procedure:
To a solution of 1.0 g of sodium (43.4 mmol) in methanol was added 1.42 g (6.8 mmol) of 1-chloro-5-nitroisoquinoline. The mixture was heated under reflux for three hours, cooled, and concentrated. The residue was partitioned between water and methylene chloride, dried, and filtered through SiO2. The filtrate was concentrated to give 1.3 g of the 1-methoxy-5-nitroisoquinoline. This material was suspended in 150 ml of methanol, 0.3 g of 5% Pd-C was added, and the mixture was hydrogenated at room temperature for 18 hours. The mixture was filtered and concentrated. The residue was crystallized from ether/hexane to give 0.32 g (27%) of the desired product; mp 53°-57°.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][NH2:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.C[O:27][C:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:40][N:35]([S:36]([CH3:39])(=[O:38])=[O:37])[C:32]1[CH:31]=[CH:30][C:29]([C:28]([NH:21][CH2:20][CH:9]2[CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:27])=[CH:34][CH:33]=1
Reactant: NCC1CN(c2ccccc2)CCN1Cc1ccccc1
Reactant: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(c1ccc(C(=O)NCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
To 4-phenyl-1-(phenylmethyl)-2-piperazinemethanamine (6.95 g, 24.7 mmol) in toluene (130 mL) at 0° C. add trimethylaluminum (2.0M in toluene, 16.2 mL, 32.4 mmol). Allow the reaction to warm to room temperature and add 4-[(methyl)(methylsulfonyl)amino]benzoic acid methyl ester (6.91 g, 28.4 mmol). Heat the reaction and monitor the progress by thin-layer chromatography. Upon completion make the solution basic with aqueous NaOH and extract with EtOAc. Remove the solvent in vacuo. Flash chromatograph the residue on silica gel with EtOAc/hexane (2/1) to obtain the title compound.
Reaction SMILES: [AlH](CC(C)C)CC(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][C:21](=O)[CH2:20][C:16]=3[NH:17][C:18]=2[CH:19]=1>C(Cl)Cl.C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[NH:17][C:18]=2[CH:19]=1
Reactant: O=C1Cc2[nH]c3cc(F)ccc3c2CCN1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc2c3c([nH]c2c1)CCNCC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flask containing THF (10 mL) at −78° C. under argon was added a 1 M solution of iBu2AlH in CH2Cl2 (16.3 mL). After 5 min, a solution of 8-fluoro-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0. 175 g, 0.80 mmol) in THF (16 mL) was added. The reaction mixture was allowed to warm to rt, stirred for 48 h, cooled to 0° C., then quenched with MeOH (4.5 mL). It was partitioned between CH2Cl2 and aqueous 1 M KO2CC(OH)C(OH)CO2Na. The CH2Cl2 extracts were washed with brine, dried, filtered, and concentrated to give a solid. The solid was purified by silica chromatography (92.5:7.5 CH2Cl2/satd NH3 in MeOH) to give the free amine. A solution of this amine (0.094 g, 0.46 mmol) in dry MeOH (4.0 mL) at rt under argon was mixed with a solution of fumaric acid (0.027 g, 0.23 mmol) in dry MeOH (2.2 mL). The turbid solution was stirred overnight at rt. The MeOH was evaporated. The residue was dissolved in hot MeOH, and the salt was permitted to crystallize. The crystalline salt was collected: mp 266° C.; MS (ESI+) m/z 205.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.94 (1H), 7.34 (1H), 7.00 (1H), 6.77 (1H), 6.40 (1H), 3.11 (4H), 2.91 (4H); Anal. C, 63.90; H, 5.83; N, 10.63.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][CH:4]=1)[CH3:12]
Reactant: C#Cc1ccc(SC)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(SC)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-methylsulfanyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (450 mg, 91% yield). 1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (d, J=8.5, 2H), 7.18-7.16 (d, J=8.5, 2H), 6.35-6.32 (d, J=11.4, 1H), 6.11-6.09 (d, J=11.4, 1H), 4.28-4.22 (q, J=7.1, 2H), 2.46 (s, 3H), 1.34-1.30 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.81, 140.87, 132.33, 127.85, 125.68, 122.81, 118.84, 101.21, 86.77, 60.37, 15.16, 14.32. Anal. Calcd. for C14H14O2S: C, 68.26; H, 5.73; S, 13.02; Found C, 68.50; H, 5.88; S, 13.18.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(F)c2cccnc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(F)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 5-fluoro-8-hydroxyquinoline-7-carboxylic acid (0.311 g) of Preparation 4 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-di-methylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxy-benzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried. The crude product is recrystallized from EtOAc/hexanes to yield 0.207 g of the title product as an off-white solid.