Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCN1c1ccc(-n2cc3c(n2)CCN(C2CCCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (45 mg, 0.15 mmol) in dichloromethane (3 ml) was added cyclohexanone (29 mg, 0.30 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 22 hours. A further 2 eq. of cyclohexanone (29 mg, 0.30 mmol) was added, and after a further 20 minutes a further 2 eq. of sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 3 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E22). MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C([CH:13](O)[C:14]([O-:16])=[O:15])C.[CH3:18]O>C1(C)C=CC=CC=1>[CH3:18][O:16][C:14](=[O:15])[CH:13]=[N:10][NH:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CO
Reactant: CCC(O)C(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)C=NNc1ccc(Cl)cc1
Yield: 82 %

Procedure:
A suspension of 4-chloro-phenylhydrazine hydrochloride (29, 16.0 g, 89.4 mmol) in anhydrous MeOH(100 mL) was treated dropwise with a solution of ethylglycolate (50% solution in toluene, 20.06 g, 98.3 mmol, 1.1 equiv) in toluene at 25° C. under N2. The resulting reaction mixture was then warmed to reflux for 12 h. When TLC and HPLC showed the reaction was deemed complete, the solvent was removed in vacuo. The residue was then treated with 50% of CH2Cl2 and hexane (v/v, 100 mL) at 25° C. for 30 min with good stirring. The pale-yellow solids were collected by filtration, washed with 50% of CH2Cl2 and hexane (v/v, 2×50 mL), and dried at 40-45° C. in vacuo for 12 h to afford the crude, desired [(4-chlorophenyl)hydrazono]acetic acid methyl ester (30, 15.6 g, 19.0 g theoretical, 82%), which was found to be pure enough to do the following reaction without further purification. For 30: CIMS m/z 211/213 (M+−H, C9H9ClN2O2).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14].[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH:21]1([NH:26][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]2[O:13][CH3:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC3CCCC3)ncnc21

Procedure:
To 1.5 g of 6-chloro-9-(2'-O-methyl-β-D-ribofuranosyl)-9H-purine and 510 mg of cyclopentylamine, 1.5 ml of triethylamine and 70 ml of ethanol were added. The solution was refluxed with heating for several ten minutes to 8 hours. After washing the residue with water, methanol was added and the solution was concentrated to dryness again. The residue was recrystallized with ethyl acetate to give N6 -cyclopentyl-2'-O-methyladenosine (Compound 1).
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].CCN(CC)CC.[C:16](OC(=O)C)(=[O:18])[CH3:17].CO>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:16]([O:8][C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[C:4]#[CH:5])(=[O:18])[CH3:17]
Reactant: C#CC(O)(CC)CC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C#CC(CC)(CC)OC(C)=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 75 %

Procedure:
In a 250-mL r.b., a solution of 3-ethyl-1-pentyn-3-ol (11.5 g, 102 mmol) in pyridine (10.2 mL) was treated sequentially with Et3N (15.0 mL, 0.107 mol, 1.4 equiv), acetic anhydride (13.5 mL, 143 mmol, 1.4 equiv), and DMAP (1.25 g, 10.2 mmol, 10.0 mol % ). The reaction mixture was stirred at rt for 5 d, then treated with MeOH (5 mL) and stirred for 1 h. The mixture was partitioned between ether (100 mL) and water (100 mL), and the aqueous layer was extracted with ether (100 mL). The organic layers were washed sequentially with 2 N NaHSO4 and brine (50 mL), dried (MgSO4), filtered, and concentrated. Distillation under reduced pressure afforded 11.8 g (58.8%) 3-ethylpent-1-yn-3-yl acetate, a colorless oil, bp 38-39° C. @ 15 mm Hg. Data for 3-ethylpent-1-yn-3-yl acetate: 1H NMR (400 MHz, CDCl3) 2.54 (s, 1 H), 2.03 (s, 3H), 1.96-2.08 (m, 2H), 1.84-1.95 (m, 2H), 0.97 (t, J=7.4, 6H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([N:35]=[N+]=[N-])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].C(Cl)Cl.CO>C1COCC1.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([NH2:35])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(N=[N+]=[N-])ncn5)ccc43)cc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(N)ncn5)ccc43)cc2)CC1

Procedure:
Hydrogenation of 0.38 mMol 5-(6-azido-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide in 10 ml THF in the presence of 70 mg Pd/C 10%, filtration, concentration of the filtrate, chromatography (Combi Flash; CH2Cl2/MeOH/NH3conc. 98:2:0→90:10:1) and crystallization from DIPE gives the title compound: MS: [M+1]+=474; TLC(EtOAc/EtOH/NH3conc. 80:20:1): Rf=0.09; Anal.: C,H,N.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1.C[OH:15]>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:6][C:7]1[CH:8]=[C:9]([C:12]([OH:15])=[O:13])[S:10][CH:11]=1
Reactant: CO
Reactant: O=Cc1cc(Br)cs1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(Br)cs1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of chromium(VI)oxide (1.57 g, 15.70 mmol) in water (3 mL) was added dropwise concentrated sulfuric acid (1.3 mL, 23.55 mmol). The formed precipitate was re-dissolved by slow addition of the minimum required amount of water and the solution was cooled with an ice bath. This solution was then added dropwise to a solution of 4-bromo-2-thiophenecarboxaldehyde (2.0 g, 10.47 mmol) in acetone (20 mL) at about 5° C. The reaction mixture was stirred at about 5° C. for about 30 minutes and then at room temperature for about 2 hours. Methanol (30 mL) was added to the reaction mixture to destroy excess oxidant and the formed solids were collected by filtration. The filtrate was concentrated under vacuum and the residue was partitioned between diethyl ether and water. The organic extract was washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum to provide the desired product. MS (DCI-NH3): m/z 206, 208 (M)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@:9]([CH:18]=[CH2:19])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:7][C@H:6]1[N:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@:9]1([CH:18]=[CH2:19])[C@@H:8]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:7][C@@H:6]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 42 h
Yield: 97.3 %

Procedure:
To a stirred solution of nucleoside 23 (3.90 g, 7.7 mmol) in anhydrous methanol (40 cm3) was added sodium methoxide (0.83 g, 15.4 mmol). The mixture was stirred at room temperature for 42 h and then neutralised with dilute aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×150 cm3), and the combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×100 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure to give nucleoside 24 as a white foam (3.48 g, 97%). δH (CDCl3) 8.89 (1H, br s, NH), 7.60 (1H, d, J 0.9, 6-H), 7.36-7.26 (10H, m, Bn), 6.23 (1H, d, J 7.8, 1′-H), 5.98 (1H, dd, J 11.2, 17.7, 1″-H), 5.66 (1H, d, J 17.7, 2″-Ha), 5.55 (1H, d, J 11.5, 2″-Hb), 4.75-4.37 (6H, m, 2′-H, 4′-H, Bn), 3.84 (1H, dd, J 2.7, 10.8, 5″-Ha), 3.58 (1H, d, J 11.2, 5′-Hb), 3.23 (1H, d, J 10.6, 2′-OH), 1.50 (3H, s, CH3). δC (CDCl3) 163.7 (C-4), 151 3 (C-2), 138.0, 136.9 (Bn), 136.0 (C-6), 131.2 (C-1″), 128.8, 128.6, 128.3, 127.8, 127.7, 127.3 (Bn), 120.7 (C-2″), 111.3 (C-5), 87.3 (C-1′), 84.6 (C-3′), 81.4 (C-4′), 78.0 (C-2′), 73.7 (C-5′), 70.0, 66.4 (Bn), 11.8 (CH3). Found: C, 66.8; H, 6.2; N, 5.9; C26H28N2O, requires C, 67.2; H, 6.1; N, 6.0%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14](SC)=[N:13][C:12]=2[CH:24]=1>N1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:13][C:12]=2[CH:24]=1
Reactant: C1CCNCC1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Solvent: c1ccncc1
Product: Clc1ccc2c(c1)N=C(N1CCCCC1)c1ccccc1N2
Temperature: 160 °C
Yield: 17.7 %

Procedure:
Piperidine (37 mg, 0.44 mmol) was added to crude 8-chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (90 mg, purity 50%, 0.218 mmol) in pyridine (2 mL) and the resulting mixture was heated in a capped tube at 160° C. for 10 h. The mixture was concentrated and flash chromatographed (SiO2, heptane:EtOAc 8:1-6:1) to give 12 mg of the title compound (166JO69A). MS (ESI) 312 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7]C)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Temperature: 70 °C

Procedure:
To a solution of methyl 3-chloro-4-hydroxybenzoate (10.0 g) in DMF (100 mL) were added potassium carbonate (14.8 g) and (bromomethyl)cyclopropane (7.80 mL), and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (50 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (54 mL), and the mixture was stirred with heating at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (11.7 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C4CCCCO4)[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:32]C4CCCCO4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[CH2:39]([NH:41][CH2:42][CH2:43][OH:44])[CH3:40].[F:45][CH2:46][CH2:47]I>>[CH2:39]([N:41]([CH2:47][CH2:46][F:45])[CH2:42][CH2:43][O:44][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:32])[CH:14]=3)[O:9]2)=[CH:6][CH:7]=1)[CH3:40]
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Reactant: FCCI
Reactant: CCNCCO
Product: CCN(CCF)CCOc1ccc(C2Oc3ccc(O)cc3C(C)=C2c2cccc(O)c2)cc1

Procedure:
The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in general procedure F, and 1-fluoro-2-iodoethane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 8.95 (s, 1H), 7.19 (d, 2H), 7.13 (t, 1H), 6.78 (d, 2H), 6.76-6.71 (m, 1H), 6.78 (d, 1H), 6.78-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.58 (s, 2H), 5.83 (s, 1H), 4.50 (t, 1H), 4.38 (t, 1H), 3.92 (t, 2H), 2.83-2.77 (m, 3H), 2.74 (t, 1H), 2.58 (q, 2H), 2.03 (s, 3H), 0.94 (t, 3H). LCMS: 464.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:24]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[O:13][CH3:24])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound from Step B (1.0 g, 3.3 mmol) in dry DMF (100 mL) at 15° C. was treated with 60% NaH (0.14 g, 3.5 mmol). After 30 min., iodomethane (47 g, 3.3 mmol) was added portionwise to the stirred solution. The reaction was stirred at room temperature for 16 hrs. and then evaporated at a temperature below 40° C. The resulting solid was chromatographed on silica gel to afford the product as a white solid; yield 0.81 g.
Reaction SMILES: [OH:1][C:2]1([CH2:20][NH:21]C(=O)OC(C)(C)C)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:11][CH:10]=2)[CH2:4][CH2:3]1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:21][CH2:20][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2cnc(-c3ccccn3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1(O)CCN(Cc2cnc(-c3ccccn3)s2)CC1

Procedure:
A solution of the compound prepared in Example 252 (0.108 g) in dichloromethane (1.3 mL) was treated with trifluoroacetic acid (0.3 mL) at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was azeotroped from toluene twice to obtain the title compound (0.104 g) having the following physical data.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:21][C:22](=[O:36])[NH:23][C:24]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:25]=4[C:26]=3[N:27]=2)[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1.CCO>[Ni].C1COCC1>[CH3:37][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:21][C:22](=[O:36])[NH:23][C:24]4[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:25]=4[C:26]=3[N:27]=2)[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1
Reactant: CN(C)CC#Cc1cnc(C(F)(F)F)c(Nc2ncc3c(n2)-c2ccc(C(F)(F)F)cc2NC(=O)C3)c1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCCc1cnc(C(F)(F)F)c(Nc2ncc3c(n2)-c2ccc(C(F)(F)F)cc2NC(=O)C3)c1
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a round bottom flask were added 2-{[5-[3-(dimethylamino)prop-1-yn-1-yl]-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.042 g, 0.081 mmol), EtOH (5 mL), THF (1 mL), and Raney nickel (20 mg). The resulting mixture was allowed to stir under a hydrogen balloon overnight. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography to give 2-{[5-[3-(dimethylamino)propyl]-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.033g, 78%) as a solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCCNc1cccnc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCNc2cccnc2)cc1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
4-geranyloxybenzoic acid(3.57 g) was dissolved in chloroform(60 ml) and triethylamine(3.60 ml), and then diphenylphosphinic chloride(2.48 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 3-(2-aminoethylamino)pyridine(2.24 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.41 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:40])(=O)=O.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][Cl:40])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)cc(I)c21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Temperature: 65 °C
Yield: 93 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (4.89 g), DMAP (209 mg) and collidine (1.59 mL) in 173 mL anhydrous DMF is heated to 65° C. to solubilize the starting material. To this solution is added methanesulfonyl chloride (2.77 mL) at room temperature. The reaction is heated at 65° C. for 2 h, then allowed to cool to room temperature. The reaction is poured into H2O (300 mL) to precipitate the product. The solid is filtered and recrystallized from CH2Cl2/hexanes to afford 4.74 g (93%) of the desired product as a white solid.
Reaction SMILES: [C:1]([C:5]1([Li])[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].O1C[CH2:14][CH2:13][CH2:12]1>>[C:1]([C:5]1[CH:9]=[CH:8][C:7](=[C:13]([CH3:14])[CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C1(C(C)(C)C)C=CC=C1
Reactant: C1CCOC1
Product: CC(C)=C1C=CC(C(C)(C)C)=C1
Reaction time: 8 h

Procedure:
Into a 200 ml, 3-neck flask, equipped with a reflux condenser, a gas inlet tube and a magnetic stirring bar, was charged, under nitrogen, 2 grams t-butylcyclopentadienyl lithium and 25 ml anhydrous tetrahydrofuran (THF). The solution was cooled in an ice-bath and 10 ml acetone, dried over 3A, was cautiously added. The reaction mixture was allowed stir overnight and quenched, cautiously, with 60 ml water. The resulting solution was extracted with ethyl ether using the standard lab extraction procedure. The resulting yellow oil was distilled under vacuum at 40-45° C. to obtain a clear yellow oil, 0.76 g.
Reaction SMILES: CC(O)(C[NH2:5])C.[CH2:7]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:23]1([CH3:29])[CH:28]=CC=C[CH:24]=1>>[CH3:24][C:23]1([CH3:29])[NH:5][C:19]2([CH2:18][CH2:17][CH:16]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:21][CH2:20]2)[O:22][CH2:28]1
Reactant: Cc1ccccc1
Reactant: CCCCCCCCCC1CCC(=O)CC1
Reactant: CC(C)(O)CN
Product: CCCCCCCCCC1CCC2(CC1)NC(C)(C)CO2

Procedure:
The procedure of Example 1 was followed utilizing 1,1-dimethylethanolamine (2.7 grams; 0.03 mole) and 4-n-nonylcyclohexanone (6.73 grams; 0.03 mole) in 100 mls of toluene. After removing the toluene, the residue was distilled to obtain 4.3 grams (48.5% of theoretical; b.p. 113°-115° C. at 0.01 mm.) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[CH:10][CH:9]=[C:8]([S:21]([N:24](CC1C=CC(OC)=CC=1)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)(=[O:23])=[O:22])[CH:7]=2)#[N:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[CH:10][CH:9]=[C:8]([S:21]([NH:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1)(=[O:23])=[O:22])[CH:7]=2)#[N:2]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(C#N)cnc3c2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1c(C#N)cnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A vial was charged with 3-cyano-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (23.3 mg, 0.043 mmol), DCM (0.5 mL), and TFA (0.25 mL). After 30 min, the mixture was diluted with MeOH and concentrated, and the crude product was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 3-cyano-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (13.6 mg, 0.032 mmol, 75.0% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.99 (br. s., 1H), 9.35 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 7.98 (dd, J=1.9, 8.8 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.67-7.58 (m, 1H), 7.40 (dd, J=1.7, 7.5 Hz, 1H), 7.35-7.28 (m, 2H), 7.21 (dt, J=0.8, 7.5 Hz, 1H), 6.89 (d, J=4.6 Hz, 1H), 3.71 (s, 3H). m/z (ESI) 423.2 (M+H)+.