Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][C@@H:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Product: CC(=O)c1cnc(Nc2ccc(C[C@H](C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al. J. Med. Chem., 1990, 33, 2231-2239.) and (2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Br:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C@H:30]3[O:34][C@@:33]([C:41]4[CH:42]=[CH:43][C:44]([Cl:48])=[CH:45][C:46]=4[Cl:47])([CH2:35][N:36]4[CH:40]=[N:39][CH:38]=[CH:37]4)[O:32][CH2:31]3)=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:15]>C(Cl)(Cl)Cl>[Br-:10].[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N+:39]2[CH:38]=[CH:37][N:36]([CH2:35][C@@:33]3([C:41]4[CH:42]=[CH:43][C:44]([Cl:48])=[CH:45][C:46]=4[Cl:47])[O:34][C@@H:30]([CH2:29][O:28][C:25]4[CH:24]=[CH:23][C:22]([N:19]5[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH3:13])[CH2:17][CH2:18]5)=[CH:27][CH:26]=4)[CH2:31][O:32]3)[CH:40]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(OC[C@@H]3CO[C@@](Cn4ccnc4)(c4ccc(Cl)cc4Cl)O3)cc2)CC1
Reactant: CC(=O)Oc1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(C[n+]2ccn(C[C@]3(c4ccc(Cl)cc4Cl)OC[C@H](COc4ccc(N5CCN(C(C)=O)CC5)cc4)O3)c2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To a solution of 28 mg of 4-acetoxybenzyl bromide in 1.5 mL of CHCl3 was added 30 mg of Ketoconazole and the mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo. Column chromatography on silica gel(Wakogel C-200, solvent:CH2Cl2/MeOH=10/1) gave 1-(4-acetoxybenzyl)-3-[(2R*,4S*)-4-[4-(4-acetyl pi perazin-1-yl)phenoxymethyl]-2-(2,4-dichlorophenyl)-[1,3]dioxolan-2-yl methyl]-3H-imidazol-1-ium bromide (32 mg, 76%, as colorless oil); MALDI-TOF-MS m/z 679 (M--Br)+; 1H-NMR(CDCl3) δ2.14(3H,s), 2.28(3H,s), 3.05(4H,m), 3.60~3.89(8H,m), 4.33(1H,m), 4.80(2H,s), 5.37(1H,d,J=14.5 Hz), 5.61(1H,d,J=14.5 Hz), 6.78(2H,d,J=9.1 Hz), 6.92, (2H,d,J=9.1 Hz), 7.03(2H,d,J=8.6 Hz), 7.24~7.63(7H,m), 10.1(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 89 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (76 mg, 89%) which was obtained as a white solid. MS: m/e=428.5 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][S-:11].[Na+]>CN(C)C=O>[CH3:10][S:11][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C[S-]
Reactant: CCOC(=O)CCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of ethyl 4-bromobutyrate (0.26 g) in N,N-dimethylformamide (3 ml) was treated with sodium thiomethoxide (0.103 g), and the mixture stirred at room temperature overnight. The mixture was partitioned between water (10 ml) and dichloromethane (10 ml), and the organic layer was washed with 1:1 saturated aqueous sodium chloride and water (10 ml). The organic layers were evaporated in vacuo to give the title compound as a clear oil (0.135 g). NMR (CDCl3) 4.06δ(2H, q, CH2), 2.46δ(2H, t, CH2), 2.35δ(2H, t, CH2), 2.03δ(3H, s, CH3), 1.85δ(2H, m, CH2), 1.18δ(3H, t, CH3).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22](=[O:24])[CH3:23])[C:14]=2[N:13]=1)C)(C)(C)C.[ClH:26]>CCOC(C)=O.O1CCOCC1>[ClH:26].[CH3:6][NH:7][CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22](=[O:24])[CH3:23])[C:14]=2[N:13]=1
Reactant: CC(=O)Nc1cccc2[nH]c(CCCN(C)C(=O)OC(C)(C)C)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNCCCc1nc2c(NC(C)=O)cccc2[nH]1

Procedure:
A solution of 1.84 g of [3-(4-Acetylamino-1H-benzoimidazol-2-yl)-propyl]-methyl-carbamic acid tert-butyl ester in 2.6 mL of EtOAc was treated with 7.75 mL of 4M-HCl in dioxane for 5 h and concentrated in vacuo to yield 1.7 g of N-[2-(3-methylamino-propyl)-1H-benzoimidazol-4-yl]-acetamide hydrochloride salt as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+]>CO>[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH2:1])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Nc1n[nH]c2ccc(NC3CCCN(Cc4ccccc4)C3)cc12

Procedure:
Reaction of tert-butyl 3,5-diamino-1H-indazole-1-carboxylate with 1-benzylpiperidin-3-one using the method of Example 8, with the modification that sodium cyanoborohydride was used as the reductant and methanol was used as the solvent, followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN1CCCC1=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=[N+]([O-])c1cc2c(cc1Cl)NCC2
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCc4cc([N+](=O)[O-])c(Cl)cc43)c2cc1OC
Yield: 24 %

Procedure:
Utilizing a procedure analogous to that described in Example 47 this product was prepared in 24% yield from 6-chloro-5-nitro-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 276°-278° C.; LC-MS: 387 (MH+); anal. RP18-HPLC RT: 4.48 min.).
Reaction SMILES: S.[Na].Cl.[Cl:4][C:5]1[C:6]([C:18]2[CH:23]=[C:22]([S:24]([CH3:26])=O)[N:21]=[C:20]([NH2:27])[N:19]=2)=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]2=[C:9]([CH:17]=1)[CH2:10][O:11][CH2:12]3.C(N(CC)C(C)C)(C)C.ClC[CH2:39][NH:40][C:41]([NH2:43])=[O:42]>CN(C)C=O.C(OC(=O)C)C>[NH2:27][C:20]1[N:21]=[C:22]([S:24][CH2:26][CH2:39][NH:40][C:41]([NH2:43])=[O:42])[CH:23]=[C:18]([C:6]2[C:5]([Cl:4])=[CH:17][C:9]3[CH2:10][O:11][CH2:12][C:13]4[C:8]=3[C:7]=2[CH:16]=[CH:15][CH:14]=4)[N:19]=1
Reactant: NC(=O)NCCCl
Reactant: CS(=O)c1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Agent: Cl
Agent: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)NCCSc1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
Sodium hydrogen sulfide (1.07 g) was dissolved in N,N-dimethylformamide (25 ml). To the mixture was added 4N hydrogen chloride in ethylacetate (13.3 ml) at room temperature. After stirring for approximately 30 minutes at the same temperature, to the resulting mixture were added 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (1.20 g) obtained in Step 5 of Example 314 and N,N-diisopropylethylamine (2.9 ml) successively. The mixture was stirred at 80° C. for four hours, and then the mixture was allowed to cool to room temperature. To the mixture were added to 2-chloro-ethylurea (3.20 g), N,N-diisopropylethylamine (5.8 ml) and N,N-dimethylformamide (15 ml) successively. The reaction mixture was stirred at 80° C. for 14 hours and then allowed to cool to room temperature. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine subsequently, dried over anhydrous sodium sulfate. After removal of inorganic salts, the solution was concentrated by evaporation. The resulting residue was purified by HPLC (column; ODS, mobile phase; 0.05% TFA in water: 0.05% TFA in acetonitrile=65:35) to give {2-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-ethyl}-urea (0.93 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6]C=1C#N.[OH-:11].[K+].C(OCCO[CH2:19][CH2:20][OH:21])C>>[F:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:19]=1[C:20]([OH:21])=[O:11]
Reactant: [OH-]
Reactant: CCOCCOCCO
Reactant: Cc1ccc(C#N)c(F)c1
Agent: [K+]
Product: Cc1ccc(C(=O)O)c(F)c1
Yield: 19 %

Procedure:
Compound of Step 1 (14 g, 105 mmol, 1 eq) was dissolved in 2-(2-ethoxyethoxy) ethanol (105 mL) and KOH (105 ml of a 8 M solution, 840 mmol, 8 eq) was added, the mixture was refluxed under nitrogen for 3 hours. The mixture was cooled and the pH set to 3. The product was extracted with EtOAc and the organic layer was washed 3 times with water and dried with sodium sulfate. The crude mixture was purified on silica using a 0-3% acetic acid/toluene gradient. 3.1 g of the desired compound (19%) was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([NH2:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:21]3[C:36](=[O:37])[C:35]4[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]3=[O:42])[CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione was prepared by the procedure of Example 5 from 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.2 mmol), sodium hydrogen carbonate (281 mg, 3.34 mmol) and N-ethoxycarbonyl phthalimide (732 mg, 3.3 mmol) in acetonitrile and water (4 mL each). The product was obtained as a white solid (314 mg, 22% yield): mp, 173.0-175.0 ° C.; 1H NMR (CDCl3); δ 1.61-2.05 (m, 8H, C5H8), 2.84 (s, 3H, CH3), 3.80 (dd, J=4.9, 14.4 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.54 (dd, J=9.9, 14.4 Hz, 1H, CHH), 4.77-4.82 (m, 1H, OCH), 5.90 (dd, J=4.9, 9.9 Hz, 1H, NCH), 6.82 (d, J=8.3 Hz, 1H, Ar), 7.09-7.17 (m, 2H, Ar), 7.69-7.75 (m, 2H, Ar), 7.81-7.86 (m, 2H, Ar); 13C NMR (CDCl3) δ 24.08, 32.77, 41.53, 48.98, 54.99, 56.03, 80.59, 111.92, 114.57, 120.37, 123.55, 129.55, 131.67, 134.20, 148.02, 150.38, 167.82; Anal Calcd for C23H25NO6S+0.1 CH2Cl2 : C, 61.38; H, 5,62; N, 3.10. Found: C, 61.05; H, 5.60; N, 2.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[C:9]([NH:8][C:4]1[CH:5]=[CH:6][C:7]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:2]([F:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1cccc(F)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Neat N-(3-fluorophenyl)acetamide (5 g, 32.65 mmol) was put on an ice-water bath and had chlorosulfonic acid added drop-wise. The solution was stirred at 0° C. for one hour, and was then stirred at room temperature overnight. The reaction was then stirred at 50° C. for four hours. The solution was then cooled to room temperature and added to a beaker of ice water. The ice was allowed to melt and then the solution was extracted with ethyl ether. The organic layer was washed with brine, then dried over sodium sulfate, and filtered. The solvent was removed under slightly reduced pressure to give 4-acetamido-2-fluorobenzene-1-sulfonyl chloride (1.50 g, 18% yield).
Reaction SMILES: [C:1]([CH:9]([Br:14])[CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][NH:20][C:19](=[S:22])[NH:18][CH2:17]1>CO>[BrH:14].[C:11]([CH2:10][CH:9]1[S:22][C:19]2=[N:18][CH2:17][N:16]([CH3:15])[CH2:21][N:20]2[C:1]1([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:13])=[O:12]
Reactant: O=C(O)CC(Br)C(=O)c1ccccc1
Reactant: CN1CNC(=S)NC1
Solvent: CO
Product: Br
Product: CN1CN=C2SC(CC(=O)O)C(O)(c3ccccc3)N2C1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of 3-benzoyl-3-bromo-propionic acid (6.4 g, 0.025 moles) in methanol (30 ml) was mixed with a solution of 5-methyl-3,4,5,6-tetrahydro-s-triazine-2(1H)-thione (3.27 g, 0.025 moles) in the same solvent (100 ml) and left for 3 hours. Evaporation of the solvent gave 7-carboxymethyl-6-hydroxy-3-methyl-6-phenyl-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide quarter hydrate as a pale yellow solid (8.8 g), m.p. 74°-77° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li][C:11](C)(C)C.[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1Br>O1CCCC1.[Cl-].[Cl-].[Zn+2].Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[C:19]1[CH:20]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[CH:26]=[CH:27][C:18]=1[C:17]([O:16][CH3:15])=[O:29]
Reactant: CSc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Reactant: [Li]C(C)(C)C
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)OC)c(-c2cc(SC)ccc2C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-Bromothioanisole (7.1 g) was dissolved in tetrahydrofuran (23 ml). To this solution at -78° C. under nitrogen was added over a ten minute period 1.7M tBuLi (48 ml). After 45 minutes at room temperature, 1M ZnCl2 (41 ml) was added dropwise over a ten minute period. After one half hour at room temperature, bis(triphenylphosphine)nickel(II) chloride (1.4 g) was added followed by dimethyl-2-bromoterepthalate (4.67 g) in tetrahydrofuran (47 ml). The reaction mixture was stirred at room temperature for 45 minutes. The THF was removed under reduced pressure. The residue was treated with ethyl acetate and 1N HCl and the layers separated. The organic phase was washed with water, brine, dried over magnesium sulfate and evaporated gave the crude product. Chromatography on silica gel using 15% ethyl acetate/hexanes gave the desired product (3.92 g).
Reaction SMILES: IC.[C:3]([O:7][C:8](=[O:17])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:18](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:3]([O:7][C:8](=[O:17])[N:9]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)[CH3:18])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 18 h

Procedure:
0.263 mL (1.1 eq.) iodomethane are added dropwise at room temperature to a stirred suspension of 1.1 g (4 mmol) (4-bromo-phenyl)-carbamic acid tert-butyl ester and 2 g (1.6 eq.) cesium carbonate in 15 mL DMF. After stirring for an additional 18 hours, the reaction mixture is extracted with water/ethyl acetate and the combined organic phases are washed with brine, dried over magnesium sulfate and evaporated to yield the desired product as a colorless oil, which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27][CH3:28])[CH:18]=4)=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([NH:38][CH2:39][C:40](O)=[O:41])(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C1C=CN=CC=1)C>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8](/[CH:7]=[CH:6]/[C:5]4[CH:29]=[CH:30][C:2]([NH:1][C:40](=[O:41])[CH2:39][NH2:38])=[CH:3][CH:4]=4)=[N:9][NH:10]3)=[CH:15][CH:14]=2)=[CH:18][C:19]=1[O:27][CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COCOc1ccc(-c2ccc3c(C=Cc4ccc(N)cc4)n[nH]c3c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc3c(/C=C/c4ccc(NC(=O)CN)cc4)n[nH]c3c2)ccc1O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3-(4-aminostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (90 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL) and was treated with Boc-glycine (196 mg, 1.12 mmol, 5 equiv), DMAP (82 mg, 3 equiv) and HATU (426 mg, 5 equiv). The mixture was allowed to stir for 30 min. The mixture was partitioned between ethyl acetate and water. The organic material was concentrated, taken up in methanol (5 mL) and was treated with potassium carbonate (100 mg). The mixture was heated to 50° C. for 3 d. The resulting mix was again partitioned between ethyl acetate and water. The organic material was concentrated, and purified by silica (109 mg, 66%): Rf sm 0.32, p 0.46 (ethyl acetate-hexane 6:4); 1H NMR (300 MHz, CDCl3) δ 8.18 (bs, 1H), 8.03 (d, 1H, J=8.1 Hz), 7.56 (m, 5H), 7.40 (m, 3H), 7.20 (m, 3H), 5.29 (s, 2H), 5.20 (bs, 1H), 3.98 (s, 3H), 3.96 (d, 2H), 3.54 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCc2ncc(OCc3ccccc3)cc21
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)cnc2CCN1c1ccccn1
Temperature: 150 °C

Procedure:
3-(Benzyloxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one, example 1.15, (10.0 mg, 0.04 mmol), 2-bromopyridine (8.0 μL, 0.08 mmol), CuI (1.1 mg, 0.006 mmol) and K2CO3 (11.0 mg, 0.08 mmol) were mixed in DMF (0.5 mL), and heated to 150° C. for 2 days. The reaction was partitioned between EtOAc (10 mL) and brine (10 mL). The organics were dried and concentrated and purified by RP-HPLC to afford the compound. LC-MS (M+H)=332.1.
Reaction SMILES: [NH2:1][C:2](C)(C)C#N.Cl[CH2:8][CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14]Cl.[NH3:17].CO>>[C:2]([C:11]12[CH2:12][CH2:13][CH2:14][N:17]1[CH2:8][CH2:9][CH2:10]2)#[N:1]
Reactant: CC(C)(N)C#N
Reactant: O=C(CCCCl)CCCCl
Reactant: N
Solvent: CO
Product: N#CC12CCCN1CCC2
Yield: 82 %

Procedure:
A mixed solution of 2-amino-2-methylpropanenitrile (41.4 g, 492 mmol) and 1,7-dichloro-4-heptanone (30.0 g, 164 mmol) in 220 ml of 16% NH3 /MeOH solution was stirred for 24 hours at 20° C. The resulting reaction mixture was concentrated in vacuo to remove MeOH therefrom, added 0.1N NaOH to the residue, which was extracted with methylene chloride, and the extract was dried over anhydrous sodium sulfate, concentrated, and distilled in vacuo to afford 18.1 g of the desired compound (Yield: 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=O.CN1CCOCC1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Solvent: CN1CCOCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Yield: 75.3 %

Procedure:
To a suspension of 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (13.3 mmol) in ethanol (60 ml) was added 4-(2-bromoacetyl)-benzoic acid (13.3 mmol) and 4-methylmorpholine (13.9 mmol). The reaction was heated at reflux for 2.5 h. The reaction was concentrated in vacuo and the solid washed with water (200 ml) to yield the title compound as a white solid (3.9 g). 1H NMR (400 MHz, CDCl3) 1.45 (9H, s), 3.58 (8H, m), 4.86 (1H, s), 6.95 (1H,s), 7.97 (2H, d, J 8 Hz), 8.1 (2H, d, J 8 Hz).
Reaction SMILES: [CH3:1][OH:2].[CH3:3][C:4]([C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:13]([OH:15])=O)([CH3:7])[CH:5]=[CH2:6].[CH:16](Cl)(Cl)Cl>>[CH2:1]([O:2][C:13]([C:9]1[NH:10][CH:11]=[N:12][C:8]=1[C:4]([CH3:7])([CH3:3])[CH:5]=[CH2:6])=[O:15])[CH3:16]
Reactant: ClC(Cl)Cl
Reactant: CO
Reactant: C=CC(C)(C)c1nc[nH]c1C(=O)O
Product: C=CC(C)(C)c1nc[nH]c1C(=O)OCC

Procedure:
Another byproduct isolated from a similar reaction (smaller scale) by further elution of the column with 5% MeOH/1% Et3N in chloroform was a compound suspected of being 5-(1,1-dimethyl-allyl)-3H-imidazole-4-carboxylic acid (0.27 g, 9%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][N:9]=1>ClCCl>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reaction time: 2 h

Procedure:
Morpholine (0.2 ml, 2.2 mmol) was added to stirred solution of 6-chloronicotinoyl chloride (250 mg, 1.4 mmol) in dichloromethane (10 ml). After 2 hours the reaction was allowed to cool and the crude mixture was applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol. The methanolic fractions were concentrated in vacuo to afford the title compound (D5).