Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([I:8])=[N:6][CH:7]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCCCCCC>[CH3:11][CH2:10][O:17][C:4]([CH3:5])=[O:9].[CH2:10]([O:9][C:4]1[C:5]([I:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cc(Br)cnc1I
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Brc1cnc(I)c(OCc2ccccc2)c1
Product: CCOC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 5-bromo-2-iodopyridin-3-ol (0.700 g, 2.334 mmol, prepared according to Bioorg. Med. Chem. Lett. 2013, 2, 6784, which is incorporated herein by reference in its entirety) in dry THF (10 ml), previously cooled to 0° C., benzyl alcohol (0.728 ml, 7.00 mmol), triphenylphosphine (PPh3) (2.095 ml, 7.00 mmol) and diisopropyl azodicarboxylate (1.287 ml, 6.54 mmol) were added. The reaction was stirred for 4 h at room temperature. Solvent was removed and the product was purified by Biotage Si 50 g with a gradient of heptane and EtOAc 3-(benzyloxy)-5-bromo-2-iodopyridine (Intermediate G25.1, 835 mg, 2.141 mmol, 92% yield) as a white foam.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][C:36]([CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[CH:37][CH:38]=1)CCC>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:34]5[O:35][C:36]([CH:39]6[O:43][CH2:42][CH2:41][O:40]6)=[CH:37][CH:38]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Solvent: C1COCCO1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6ccc(C7OCCO7)o6)cc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine (4.3 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)furan (J. Chem. Soc., Chem Commun., (1988), 560) (10 g) and 1,4-bis(diphenylphosphino) palladium (II) chloride (1 g) in dioxane. The solvent was removed in vacuo and the residue chromatographed on silica. Subsequent trituration gave the title compound δH [2H6]-DMSO 10.13 (1H, s), 8.85 (1H, s), 8.54 (1H, s), 8.20 (3H, m), 7.80 (3H, m), 7.30 (5H, m), 7.13 (1H, d), 6.79 (1H, d), 6.04 (1H, s), 5.71 (2H, s), 4.15 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC[C:14]([O-:16])=O.[NH3:17]>C(O)C>[F:1][C:2]1[C:11]2[O:10][CH:9]([C:14]([NH2:17])=[O:16])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1cccc2c1OCCN2
Reactant: CCC(=O)[O-]
Solvent: CCO
Product: NC(=O)C1CNc2cccc(F)c2O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5b (1.1 g, 4.89 mmol) in ethanol (20 mL) an ammonia solution is added (32%, 5 mL). The solution obtained is agitated 14 h at ambient temperature then 10 mL of ammonia are added and the mixture agitated for 48 h. The solution is concentrated under reduced pressure and the residue is dissolved in petroleum ether. The formed precipitate is filtered, washed in petroleum ether and vacuum dried (0.75 g, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:4](=[O:16])[CH:3]=1.C1C(=O)N([Cl:24])C(=O)C1>C(Cl)Cl>[Cl:24][C:3]1[C:4](=[O:16])[N:5]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Cc1cc(O)cc(=O)n1Cc1cccnc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(O)c(Cl)c(=O)n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 224.1 %

Procedure:
To a suspension of 4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (1.016 g, 4.7 mmol) in MeCl2 (10 mL) was added NCS (1.21 g, 1.78 mmol). The reaction mixture stirred at room temperature for 24 hours under nitrogen. The suspension was chilled in an ice bath and filtered. The solid was washed with fresh MeCl2 and dried to afford a yellow solid (1.00 g, 85%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.54 (m, 2H), 7.85 (d, 1H, J=1.6 Hz), 7.61 (m, 1H), 6.10 (s, 1H), 5.41 (s, 2H), 2.33 (s, 3H); ES-LRMS (M+H) m/z 251/253.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[NH2:34][CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[OH:37][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: NC[C@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NC[C@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccncc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, the title compound was obtained in 66% purity by HPLC. MS(ESI+): m/z=459.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10]>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:10][CH2:9][C:8]([N:7]([CH3:12])[CH3:6])=[O:11])[CH3:2]
Reactant: C=CC(=O)N(C)C
Reactant: CCNCC
Product: CCN(CC)CCC(=O)N(C)C
Yield: 86 %

Procedure:
In accordance with this example, anhydrous diethylamine (44 grams) and N,N-dimethylacrylamide (60 grams) were heated at reflux temperature (about 56°-60°C.) for 48 hours. After this period of time, the reaction mixture was subjected to distillation to separate unreacted amine and amide followed by recovery of product in 86 percent yield at 70°C. and 2 mm. mercury pressure. The liquid product (purity = about 95 percent is designated herein as Amine Catalyst V, and has the formula, (C2H5)2N-CH2CH2C(O)N(CH3)2. The structure of this novel product was confirmed by infrared functional analysis and purity by gas-liquid chromatographic analysis.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl[CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: OCCOCCOCCCl
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOCCOCCO)cccc2c1Nc1ccccc1C
Yield: 68.4 %

Procedure:
A mixture of 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (2.40 g, 7.5 mmol), potassium t-butoxide (1.22 g, 10 mmol) and 2-(2-(2-(chloroethoxy)ethoxy)ethanol (2.18 ml, 15 mmol) in tetrahydrofuran (40 ml) was heated at reflux for 3 days. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 0-10% methanol in ethyl acetate) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)quinoline (2.32 g, 68%) as a hygroscopic solid, m.p. 102°-104°.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 118-133, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 379.2235.
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]3[C:14](=[O:15])[N:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=4)[N:12]=[C:11]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH2:63]>CC(N(C)C)=O>[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH:63][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([N:13]2[C:14](=[O:15])[C:10]3=[CH:9][S:8][C:7]4[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=4[C:11]3=[N:12]2)=[CH:17][CH:18]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(6-Fluoro-3-oxothiochromeno[4,3-c]pyrazol-2(3H)-yl)benzoic acid (41 mg, 0.12 mmol) was dissolved in anhydrous dimethyl-acetamide (1 ml). Diisopropyl-ethyl amine (46 mg, 0.36 mmol, 62 μl) was added followed by [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (65 mg, 0.17 mmol) and 3-dimethylaminopropylamine (12 mg, 0.12 mmol). The mixture was stirred at room temperature overnight and purified by preparative HPLC. The title compound was isolated as a brown solid. LCMS: m/z 425 [M+H]+. Activity **
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8]O[C:6](=O)[CH:5]=1)[CH3:2].[C:16]1(=[O:23])C=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1>C1C(Cl)=CC=C(Cl)C=1.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:20](=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:19](=[O:22])[CH:18]=[CH:17][C:16]2=[O:23])[CH3:2]
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)c1coc(=O)cc1OCC
Agent: O=[Mn]=O
Solvent: Clc1ccc(Cl)cc1
Product: CCOC(=O)c1cc2c(cc1OCC)C(=O)C=CC2=O

Procedure:
0.42 g (0.002 mol) of ethyl 4-ethoxy-2-oxo-2H-pyran-5-carboxylate, 1.08 g (0.01 mol) of 1,4-benzoquinone and 0.54 g (0.0062 mol) of MnO2 in 4.8 ml of dichlorobenzene are heated at 180° C. for 12 hours. The resulting reaction mixture is chromatographed over a column of 30 g of silica gel 60 (mobile phase 99:1 CH2Cl2 /acetone, 0.3 bar excess pressure). This gives 0.41 g (75.9%) of crystals of melting point 60°-62° C.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:22][C:21]4[C:16](=[C:17](I)[CH:18]=[C:19]([Cl:23])[CH:20]=4)[C:15]3=[O:25])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Cu][C:28]#[N:29].ClCCl.C(O)C>CN(C)C=O>[Cl:23][C:19]1[CH:18]=[C:17]([C:28]#[N:29])[C:16]2[C:15](=[O:25])[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:26])([F:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)[CH2:22][C:21]=2[CH:20]=1
Reactant: N#C[Cu]
Reactant: O=C1c2c(I)cc(Cl)cc2CN1C1CCN(C2CCC(F)(F)CC2)CC1
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Yield: 73 %

Procedure:
2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-5-chloro-7-iodo-2,3-dihydro-1H-isoindol-1-one (80 mg, 0.16 mmol) and copper(I) cyanide (22 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1 mL) and the resulted solution was refluxed under nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:95/5) afforded title compound (46 mg, 72% yield).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-:25].[K+].[K+]>>[F:9][CH:8]([F:10])[C:4]1[C:3]([C:11]([OH:12])=[O:25])=[C:2]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:22])([F:23])[F:13])=[CH:20][CH:19]=2)[N:6]([CH3:7])[N:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde and 4-(trifluoromethyl)phenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)[CH:6]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.61) (0.16 g, 0.42 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.06 g, 36%). MS (ISP) 397.1 [(M+H)+]; mp 213° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[N:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][C:15]1[C:24]2[C:23](=[O:25])[CH:22]=[CH:21][C:20](=[O:26])[C:19]=2[NH:18][C:17](=[O:27])[CH:16]=1>C(Cl)(Cl)Cl>[CH3:14][C:15]1[C:24]2[C:23](=[O:25])[C:22]3[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH:5]=[CH:4][NH:3][C:21]=3[C:20](=[O:26])[C:19]=2[NH:18][C:17](=[O:27])[CH:16]=1.[CH3:1][N:2]([CH3:13])[C:22]1[C:23](=[O:25])[C:24]2[C:15]([CH3:14])=[CH:16][C:17](=[O:27])[NH:18][C:19]=2[C:20](=[O:26])[CH:21]=1
Reactant: Cc1cc(=O)[nH]c2c1C(=O)C=CC2=O
Reactant: CN(C)N=C/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)[nH]c2c1C(=O)C(N(C)C)=CC2=O
Product: Cc1cc(=O)[nH]c2c1C(=O)C1=C(NC=CC1c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
A solution of 233 mg (1.34 mmol) of trans-cinnamaldehyde N,N-dimethylhydrazone was added to a solution of 4-methyl-1H-quinoline-2,5,8-trione (127 mg, 0.67 mmol) in dry chloroform (120 ml). The reaction was stirred under nitrogen at room temperature for 3 days, with periodical additions of solvent (100 ml each 12 h). A further amount of 166 mg (0.61 mmol) of the hydrazone was added, and the reaction was refluxed for 24 h and evaporated to dryness, and the residue was purified by silica gel chromatography using a gradient elution, starting with neat dichloromethane to dichloromethane/ethyl acetate (7:3), to yield 204 mg of the starting diene, 72 mg (35%) of 2 and 160 mg of 6-dimethylamino-4-methyl-1H-quinoline-2,5,8-trione.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[C:8]([N+:13]([O-])=O)[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[O:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[F:16][C:2]1([F:1])[O:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([NH2:13])=[CH:7][C:5]=2[O:6]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(F)(F)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)OC(F)(F)O2
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
2,2-Difluoro-5-methoxy-6-nitrobenzo[d][1,3]dioxole (1.7 g, 7.3 mmol) was dissolved in ethyl acetate (50 mL) and treated with 5% palladium on carbon (200 mg) and hydrogen at 40-50 pounds per square inch (psi) on a shaker. After 90 min, the catalyst was removed by filtration, the solvent was removed by evaporation, and the product dried under vacuum to give the title compound as a brown solid (1.5 g, qt (quantitative)): 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.50 (s, 1H), 3.82 (s, 3H), 3.76 (d, J=23.0 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −50.32 (s); EIMS m/z 203.
Reaction SMILES: [NH4+].[OH-].S[C:4]1[N:5]=[C:6]([OH:14])[C:7]2[C@H:12]([CH3:13])[CH2:11][CH2:10][C:8]=2[N:9]=1>[Ni].O>[CH3:13][C@H:12]1[C:7]2[C:6]([OH:14])=[N:5][CH:4]=[N:9][C:8]=2[CH2:10][CH2:11]1
Reactant: C[C@@H]1CCc2nc(S)nc(O)c21
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CCc2ncnc(O)c21
Yield: 100.1 %

Procedure:
Raney Nickel (15 g) and NH4OH (20 mL) was added to a suspension of (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-ol (12 g, 65.8 mmol) in distilled water (100 mL). The mixture was refluxed for 3 hours and then filtered. The filtrate was concentrated to afford (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.89 g, 99%). MS (APCI+) [M+H]+151.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+].[H][H]>[Ni].CO>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#N
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CN
Reaction time: 2 h
Yield: 630.9 %

Procedure:
Raney nickel (˜0.5 g) was added to a solution of 2-cyano-4-chlorophenoxy acetic acid-t-butyl ester (560 mg, 0.21 mmol) in methanol (25 mL) containing 1 mL of sat. ammonium hydroxide. The mixture was placed under 40 psi of hydrogen and shaken for two hours. The mixture was filtered and concentrated. The residue was partitioned between 1 N HCl and ether. The layers were separated and the aqueous layer was re-extracted with ether. The aqueous layer was basified to ˜pH with K2CO3 solution and extracted with ether (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford 360 mg of the title compound as an oil. MS 272 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H); 7.12 (d, 1H, J=8.7 Hz); 6.61 (d, 1H, J=8.7 Hz); 4.5 (s, 2H); 3.85 (s, 2H); 2.62 (bs, 2H); 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10]([Cl:22])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Cl)nc1Cl)C(=O)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(Oc1ccc(Cl)nc1Cl)C(=O)Cl

Procedure:
23.6 g (0.1 mole) of 2-[(2,6-dichloro-3-pyridyl)oxy]propionic acid, 150 ml of chloroform and 1.5 ml of dimethylformamide were heated with stirring at 55°, and an addition was then made dropwise in the course of 1 hour of a solution of 18 g (0.15 mole) of thionyl chloride in 40 ml of chloroform. The reaction mixture was subsequently refluxed for 16 hours and afterwards concentrated in vacuo. The resulting product was used directly for further reactions.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>C1(C)C=CC=CC=1.O1CCOCC1.O=[Mn]=O>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:11]([CH:12]=[O:13])=[CH:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)sc1ncc(CO)n12
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)sc1ncc(C=O)n12
Yield: 68.9 %

Procedure:
A suspension of 7-Methyl-imidazo[2,1-b]benzothiazole-3-methanol (Formula K-2) (0.82 g) in hot toluene (100 mL) was diluted with dioxane (10 mL) to effect dissolution of 7-Methyl-imidazo [2,1b]benzothiazole-3-methanol (Formula K-2). The solution was treated with activated MnO2 (1.64 g) and azeotropically distilled for 1.25 hours. The suspension was filtered, the cake was washed with hot ethyl acetate, and the filtrate was evaporated to a crystalline solid (0.69 g). Crystallization from isopropanol gave pure 7-Methyl-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula K-3) (0.56 g), m.p. 170-171°.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].C(N(CC)CC)C.[C:42]([NH:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][C:54](O)=[O:55])[CH2:48][CH2:47]1)(=[O:44])[CH3:43].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:42]([NH:45][CH:46]1[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][C:54]([NH:1][CH2:2][C:3]([N:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]3[C:24]4[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:20]=4[CH:19]=[CH:18][CH:17]=3)[C:8]=2[Cl:34])[CH3:6])=[O:4])=[O:55])[CH2:50][CH2:51]1)(=[O:44])[CH3:43]
Reactant: CC(=O)NC1CCN(CCC(=O)O)CC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCN4CCC(NC(C)=O)CC4)c3Cl)cccc2n1Cc1ccccn1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.30 g, 0.60 mmol) in anhydrous DMF (15 mL) was added triethyl amine (0.067 g, 0.66 mmol) under nitrogen at 0° C. The mixture was stirred for 30 min and was added 3-(4-acetamidopiperidin-1-yl)propanoic acid (0.257 g, 1.20 mmol) and HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) (0.296 g, 0.78 mmol). The mixture was stirred at room temperature overnight, evaporated, mixed with a saturated brine solution and extracted with ethyl acetate. Evaporation gave a crude oil that was purified using silica chromatography eluting with a gradient of 2% to 30% DCM (dichloromethane)/MeOH/NH4OH (10:1:0.1). After drying at 78° C. under high vacuum, 3-(4-acetamidopiperidin-1-yl)-N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)propanamide, 8, was isolated as a solid (0.23 g, 55%). LCMS (+ESI) 696 (M+1). 1H-NMR (CDCl3, δ ppm): 8.96 (bs, 1H), 8.59 (m, 1H), 7.58 (t, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27 (m, 1H), 7.19 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.82 (m, 1H), 5.66 (m, 2H), 5.48 (bd, 1H), 5.28 (s, 2H), 4.20 (s, 3H), 3.85 (m, 2H), 3.54 (dd, J=18, 3.6 Hz, 1H), 3.26 (s, 3H), 2.96 (bd, 2H), 2.62 (m, 2H), 2.37 (m, 2H), 2.14 (m, 2H), 1.97 (s, 3H), 1.96 (m, 3H). Calcd. for C34H39Cl2N7O5+1.4H2O: C, 56.57; H, 5.84; N, 13.58. Found: C, 56.44; H, 5.59; N, 13.48.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[S:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[ClH:11].[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:13][NH2:14])[C:5]=2[S:4][CH:3]=1
Reactant: NN
Reactant: Clc1ncnc2c(Br)csc12
Solvent: O
Solvent: CCO
Product: Cl
Product: NNc1ncnc2c(Br)csc12
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A suspension of 7-bromo-4-chlorothieno[3,2-d]pyrimidine (159, 80 mg, 0.32 mmol) and hydrazine monohydrate (0.2 mL, 4.1 mmol) in ethanol (1.3 mL) was heated at reflux for 2 hour. After cooling to room temperature, the solid product was collected by vacuum filtration to give (7-bromothieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (57 mg, 73% yield) as a white solid.