Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[N:10]=[C:11]([CH3:24])[N:12]=[C:13]([NH:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[N:7]=[N:6]1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C)C=O.O>[CH2:27]([N:14]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[C:13]1[C:8]2[N:7]=[N:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:9]=2[N:10]=[C:11]([CH3:24])[N:12]=1)[CH3:28]
Reactant: COCCn1nnc2c(Nc3c(C)cc(C)cc3C)nc(C)nc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1c(C)cc(C)cc1C)c1nc(C)nc2c1nnn2CCOC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from Example 38, Part B (150 mg, 0.46 mmol) was treated with sodium hydride (17 mg, 0.55 mmol, 80%) and ethyl iodide (55 ml, 0.69 mmol) in dry dimethylformamide (3 ml) and stirred at room temperature for 48 h. The reaction was diluted with 50 ml water, and extracted with 4-30 ml methylene chloride. The combined organic extracts were dried over anydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (50 g, 1/1 hexanes/ethyl acetate) afforded the desired product, 144 mg (88%) as a clear viscous oil. CI-HRMS calcd. for C19H27N6O1 (M+H): 355.2246. Found: 355.2240.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:8]1)[CH2:6][C:5]2=O.[C:20](=[N:26][Si](C)(C)C)=[N:21][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH2:8]1)[CH2:6][C:5]2=[N:26][C:20]#[N:21]
Reactant: CC(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)C1CCC2(CC(=NC#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentan]-4-one (250 mg, 0.776 mmol) in DCM (10 mL) was added TiCl4 (1.55 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.38 mL, 1.707 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide (250 mg, 93%). 1H-NMR (CDCl3): 0.82 (m, 6H), 1.36 (m, 2H), 1.69 (m, 3H), 1.96 (m, 3H), 3.10 (d, 2H), 6.75 (m, 1H), 7.52 (m, 1H), 8.04 (d, 1H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.O>CS(C)=O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=[C:2]1[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: Cn1c(=O)c2c(nc(Br)n2Cc2c(F)cccc2Cl)n(C)c1=O
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(nc(N3CCCC3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.12 mmol) in 300 μL DMSO was treated with pyrrolidine (55 μL, 0.55 mmol) and heated at 130° C. for 15 h. The reaction was cooled to 25° C. and treated with 1 mL H2O. After centrifugation for 1 h the liquid was decanted, and the process was repeated. The reaction was treated with 1 mL toluene and concentrated under reduced pressure. The residue was treated with 2 mL CH2Cl2 followed by isocyanate scavenger resin (500 mg, 0.58 mmol, 1.16 mmol/g). The reaction was filtered after agitating for 30 min, and the filtrate was concentrated under reduced pressure to give 48 mg (>99% yield) of the title compound: 1H NMR (CDCl3, 300 MHz) 7.27-7.18 (m, 2H), 7.02-6.91 (m, 1H), 5.73 (s, 2H), 3.59-3.48 (m, 7H), 3.35 (s, 3H), 1.98-1.87 (m, 4H); MS (ESP+) m/e 392 (MH+); TLC (EtOAc:hexanes/1:1) Rf=0.24.
Reaction SMILES: O[C:2]1([CH3:18])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[NH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[CH3:18][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: CC1(O)c2ccccc2NC(=O)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC1c2ccccc2CNc2ccccc21
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
11-Hydroxy-11-methyl-5,11-dihydro-dibenzo[b,e]azepin-6-one (3) (51.6 g 0.22 mol) was added to a suspension of LiAlH4 (33 g, 0.88 mol) in dioxane (850 mL). The reaction mixture was heated to 105° C. After 2.5 h under reflux the reaction mixture was cooled, the excess LiAlH4 was destroyed with aqueous Na2SO4 (55 mL). ethyl acetate (1.81) and Na2SO4 (440 g) were added, the reaction mixture was stirred for 30 min. The solids were filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Heptane:Ethyl acetate=6:4) to give 6,11-dihydro-11-methyl-5H-dibenzo[b,e]azepine (4) (28 g, 61%) Data: (m/z)=210 (M+H)+.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]CC=C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+]>C(O)C.O>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: C=CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Yield: 91.4 %

Procedure:
According to the general saponification procedure, 6.11 g crude Boc-D-Leu-Leu-OAllyl were saponified with 3 g sodium hydroxide in ethanol/water to yield 5.0 g crude Boc-D-Leu-Leu-OH which was used in the next step without purification
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Br)cc1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(Br)cc2)nc(N)n1
Yield: 84 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-bromoaniline provided the title compound (84% yield). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3), 6.10 (s, 1H, Ar), 6.45 (s, 2H, NH2), 7.31 (d, 1H, J=8.3 Hz, Ar), 7.37 (dd, 1H, J=8.2 Hz, J=2.3 Hz, Ar), 7.41 (d, 1H, J=2.3 Hz, Ar), 7.43-7.45 (m, 2H, Ar), 7.78-7.75 (m, 2H, Ar), 9.35 (s, 1H, NH).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10]1)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([CH3:22])[C:14]2=[O:23])[CH2:10]1
Reactant: Cn1c(=O)n([C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)c2ncccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 51 %

Procedure:
Hydrogen chloride, 4.0M solution in 1,4-dioxane (130 mL, 519 mmol) was added to a stirred solution of the tert-butyl(trans-3-(1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)cyclobutyl)carbamate product of step 2 (33.1 g, 104 mmol) in 1,4-dioxane (400 mL). The reaction mixture was stirred at room temperature for 21 h. The precipitate was filtered and washed with ether to yield the title compound (13.4 g, 51% yield) as an off-white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:41]=[CH:40][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:28]([C:31]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)=[O:32])=[CH:29][CH:30]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:7]2[CH:41]=[CH:40][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[C:21]([C:24]([OH:26])=[O:25])[CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:28]([C:31]([N:33]5[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]5)=[O:32])=[CH:29][CH:30]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1ccc(C(=O)N3CCN(C)CC3)n1C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc3n2Cc2ccc(C(=O)O)cc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the methyl 10-(4-cyclohexylbenzoyl)-3-[(4-methyl-1-piperazinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylate of Example 1, Step D (1.1 g, 1.93 mmol) in ethanol (10 mL) was added 2.5 N sodium hydroxide (1.5 equiv.) and the reaction mixture was stirred overnight at room temperature. The solution was neutralized by the addition of one equivalent of 2 N hydrochloric acid and the solvent was removed in vacuo. The residue was extracted with dichloromethane, filtered and the solvent removed in vacuo. The residue was then chromatographed on silica gel eluting with 10% methanol in dichloromethane to provide the title product as a white crystalline solid, m.p. 195–210° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[C:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([S:19](Cl)(=[O:21])=[O:20])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].Cl>N1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([NH:1][S:19]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
2-Amino-5-tert-butyl-1,3,4-thiadiazole (1.0 g, 6.36 mmol) was suspended in pyridine (1.6 mL). N-Acetylsulfanilyl chloride (1.9 g, 5.1 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3N HCl and the mixture extracted with ethyl acetate. The organic extracts were washed with water (3×65 mL), brine (3×65 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated. The residue was crystallized from MeOH to give the product (1.59 mg, 4.3 mmol, 84%) as a solid, mp 137-138° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (9, t, J=7.0 Hz), 2.08 (3, s), 7.73 (2, d, J=8.5 Hz), 7.78 (2, d, J=8.5 Hz), 10.48 (1, s), 14.00 (1, brs); 13C NMR (125 MHz, DMSO) δ 24.1, 29.3, 36.1, 118.6, 126.8, 135.6, 142.8, 166.9, 167.2, 169.0; MS (LCQ, ESI+) Calculated for C14H19N4O3S2 355.1. found 355.1 (M+H)+. HRMS (FAB+, m/z) Calculated for C14H19N4O3S2 355.0899. found 355.0900 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([NH2:7])=O>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:13])([F:14])[F:15])[C:5]#[N:7]
Reactant: NC(=O)c1ccc(OC(F)(F)F)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 85 °C
Yield: 85 %

Procedure:
750 ml of SOCl2 were added to 239.5 g (1 mol) of 3-chloro-4-trifluoromethoxybenzamide and the mixture was heated slowly (corresponding to the evolution of gas) to 85° C. The mixture was then fractionally distilled and 189 g of product having a boiling point at 13 mbar of 96° C. and a melting point of 38° to 40° C. were obtained. This corresponds to a yield of 85% of theory.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[I:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Ic1ncnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21

Procedure:
610 mg (2.49 mmol) of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 2.5 mL DMF. 110 mg (2.74 mmol) of 60% sodium hydride was added followed by 480 μL (2.74 mmol) of trimethylsilylethoxymethyl chloride. Yield: 750 mg of an oily product, 90% pure.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:1]3[CH:2]=[CH:3][C:4]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:5][CH:6]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1ccc(-c2ccnc(Nc3ccccc3)n2)cc1
Solvent: O
Product: O=S(=O)(Cl)c1ccc(Nc2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A solution of N-phenyl-4-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine (0.16 g, 0.5 mmol) in 1.5 ml of chlorosulfonic acid is stirred at 65 to 70° C. for 1 hr. It is then cooled to room temperature, and added slowly to a stirred mixture of ice and water. The resulting suspension is filtered, and the precipitate is washed with water and then dried in vacuo to give 0.24 g of a yellow solid; mp 186-188° C.; HRMS: calcd for C17H11ClF3N3O2S, 413.0213; found (ESI-FTMS, [M+H]1+), 414.02984.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH2:15]1[CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:18][C:17]=2[O:16]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][CH:25]([C:19]4[CH:20]=[CH:21][C:22]5[O:23][CH2:24][CH2:15][O:16][C:17]=5[CH:18]=4)[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1cc2c(cc1C1CCNCC1)OCCO2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: c1cc(OCCCN2CCC(c3ccc4c(c3)OCCO4)CC2)c2cc[nH]c2c1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(3,4-ethylenedioxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 59% overall yield as a foam. FDMS m/e=392 (M+ of free base).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17](=[O:20])[CH2:18]Cl)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:14][CH2:18][C:17](=[O:20])[NH:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCC1(O)CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1COC2(CCN(Cc3ccccc3)CC2)CN1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 62.1 %

Procedure:
To a mixture of compound 398 (41.9 g, 141 mmol) in tetrahydrofuran (300 mL) was added potassium tert-butoxide (31.8 g, 283 mmol), portionwise over 40 minutes. After 3.5 hours of stirring at room temperature, the reaction was concentrated in vacuo. The residue was diluted with DCM and water, and then neutralized with 3N HCl. The remaining solids were filtered off and the filtrate was concentrated to an oil. The residue was taken up in hot ethanol (100 mL). After allowing the solution to cool to ˜45° C., the salts were filtered off, and the filtrate was concentrated to a brown solid. The crude material was purified by flash chromatography (0-20% methanol in DCM with 1% NH4OH) to give compound 399 as an orange solid (22.8 g, 62%). LCMS-ESI (POS), M/Z, M+1: Found 261.1, Calculated 261.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=3[N:12]=2)=[CH:8][CH:7]=1)[CH3:4].Cl[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>O1CCOCC1>[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[N:12]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:13]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCN(CC)CCCl
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1ccc(Cc2nc3ccc([N+](=O)[O-])cc3n2CCN(CC)CC)cc1
Temperature: 65 °C
Yield: 13.6 %

Procedure:
To a small, argon purged flask fitted with a condenser and magnetic stirbar is charged Sodium Hydride (60 wt %, 74 mg, 1.850 mmol) and anhydrous dioxane (5 mL) and stirring begun. A solution of 2-(4-Ethoxy-benzyl)-5-nitro-1H-benzimidazole 42 (550 mg, 1.850 mmol) in anhydrous dioxane (10 mL) was added dropwise to the suspension of sodium hydride and the mixture heated to 65° C. for 90 minutes at which time a solution of (2-Chloroethyl)-diethyl-amine (251 mg, 1.850 mmol) in anhydrous dioxane (5 mL) is added dropwise to the hot solution. After 60 minutes at 65° C. the mixture is cooled to room temperature, filtered and solvent removed under reduced pressure to afford crude. The product was purified using dry silica gel column chromatography eluting with 25 mL portions of solvent system (1.25% 2M NH3 in methanol/98.75% dichloromethane to 2.5% 2M NH3 in methanol/97.5% dichloromethane). The enriched fractions were further purified using silica gel column chromatography eluting with 50% ethyl acetate/50% hexanes to 70% ethyl acetate/30% hexanes to afford a pale yellow-colorless solid 43 {2-[2-(4-Ethoxy-benzyl)-6-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine Yield: 100 mg (13.6%). 1H NMR (DMSO) δ: 0.70 (t, 6H, J=7.1), 1.30 (t, 3H, J=6.9), 2.39 (q, 4H, J=7.1), 2.50 (m, 2H), 3.98 (q, 2H, J=6.9), 4.28-4.36 (s, 2H; m, 2H) 6.87 (d, 2H, J=8.7), 7.20 (d, 2H, J=8.6), 7.72 (d, 1H, J=9.0), 8.06 (dd, 2H, J=8.9, 2.1), 8.51 (d, 1H, J=2.1); MS (ESI): 397 (MH+, 100%).
Reaction SMILES: [H][H].C([SiH](CC)CC)C.[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][CH:17]=[CH:16][C:15]=2[CH:19]=1.FC(F)(F)C(O)=O>>[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][CH2:17][CH2:16][C:15]=2[CH:19]=1
Reactant: [H][H]
Reactant: Oc1ccc2sccc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCS2

Procedure:
Scheme I depicts the preparation of the simplest member (2) of the invention, that is where R4 and R6 are both hydrogen. Triethylsilane is reacted with 5-hydroxybenzothiophene in a suitable solvent, e.g, trifluoroacetic acid (TFA) to yield the 5-hydroxy-2,3-dihydrobenzothiophene. ##STR4##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]=[O:11])[S:7][C:6]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:4].[BH4-].[Na+]>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:10][OH:11])[S:7][C:6]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:4]
Reactant: COC(=O)c1cc(C=O)sc1NC(=O)c1ccc(OC)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)sc1NC(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
Crude 2-(3,4-dimethoxy-benzoylamino)-5-formylthiophene-3-carboxylic acid methyl ester (35 mg) synthesized by the above process was dissolved in tetrahydrofuran/N,N-dimethylformamide=1/1 (10 ml). Sodium borohydride (22 mg) was added to the solution at room temperature, and the mixture was stirred at that temperature for 20 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to give crude 2-(3,4-dimethoxy-benzoylamino)-5-hydroxymethyl-thiophene-3-carboxylic acid methyl ester (35 mg, crude yield 100%).
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.[Br:22][C:23]1[CH:28]=[C:27]([CH2:29]Br)[CH:26]=[CH:25][C:24]=1[F:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[F:31])[CH2:29][N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20]
Reactant: Fc1ccc(CBr)cc1Br
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1ccc(F)c(Br)c1

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 106 mg of 2-bromo-4-(bromomethyl)-1-fluorobenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 50 mg of (2S)-1-(3-bromo-4-fluorobenzyl)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of a off-white semi-solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Br:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[N:10]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:9]
Reactant: Brc1cccc(Br)c1
Reactant: CNC1CCCC1
Product: CN(c1cccc(Br)c1)C1CCCC1

Procedure:
The title compound was prepared from 1,3-dibromobenzene and N-methylcyclopentanamine using a similar procedure to that described for D43. LCMS (A): m/z (M+H)+ 254/256, Cl2H16BrN requires 253/255 (acidic).
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]2[NH:12]C(=O)[NH:14][S:15](=[O:17])(=[O:16])[C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>OS(O)(=O)=O>[NH2:12][C:11]1[CH:19]=[CH:20][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[S:15]([NH2:14])(=[O:16])=[O:17]
Reactant: O=C1Nc2ccc(Oc3ccccc3)cc2S(=O)(=O)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2ccccc2)cc1S(N)(=O)=O
Temperature: 105 °C
Yield: 24.5 %

Procedure:
A mixture of 7-phenoxy-1,1-dioxo-1,4-dihydro-2-H-benzo[1,2,4]thiadiazin-3-one (18.0 g, 61.8 mmol) in aqueous H2SO4 (50% v/v, 1 L) was heated at 105° C. for 7 h. The clear solution was then cooled to 0° C. and neutralized using 5N NaOH. The product was extracted with ethyl acetate. The combined extracts were washed with water and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) to afford the title compound (4.0 g, 24%).