Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11](#[N:13])[CH3:12].[O:14]1[CH2:19][CH2:18][CH:17]([C:20](OC)=[O:21])[CH2:16][CH2:15]1.Cl>C1COCC1>[O:21]=[C:20]([CH:17]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)[CH2:12][C:11]#[N:13]
Reactant: CC#N
Reactant: COC(=O)C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
26.8 ml of a 1M solution of LiHMDS in THF are introduced into 25 ml of anhydrous THF under an argon atmosphere. The mixture is maintained at a temperature of about −78° C., and then 1.47 ml of acetonitrile in solution in 3 ml of anhydrous THF are added. The reaction mixture is kept stirring at −78° C. for 40 minutes and then a solution of 3.0 g of methyl tetrahydropyran-4-carboxylate in 3 ml of THF is added. After stirring for 2 hours at −78° C., the mixture is left to return to ambient temperature for 15 hours and it is then diluted with 200 ml of a water/ice mixture. The pH is adjusted to a value of about 3 by adding 2N HCl, and then the mixture is extracted three times with 150 ml of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to give 3.18 g of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile in the form of a light brown oil.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:8][CH2:9][CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[O:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].[Cl-].[NH4+]>CN(C=O)C>[C:22]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH2:9][CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:15]=3[O:14][CH2:13][CH2:12]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1cccc2c1OCCN2CCOC(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1OCCN2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
4-(2-(diphenylmethoxy)-ethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazine (161 mg) was dissolved in anhydrous DMF (4 ml), and anhydrous potassium carbonate (54 mg) and methyl bromoacetate (0.04 ml) were added to the resultant solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate containing 15% n-hexane. The resultant organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The resultant residue was purified by medium-pressure column chromatography (solvent:ethyl acetate:cyclohexane=1/3) to obtain the colorless oily object compound (118 mg, yield 97%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21](=[CH2:1])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(=O)c1c(OC)cccc1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (61.1 g, 1.2 equiv) in THF (350 ml) at 0 C was added potassium bis(trimethylsilyl)amide (260 ml of a 15% solution in toluene, 1.2 equiv) and this mixture was stirred at 0 C for 15 min and at r.t. for 45 min. Then, a solution of the ketoester 16 (33.7 g, 141 mmol) in THF (70 ml) was added at 0 C and stirring was continued at r.t. for 1 h. The reaction was quenched by addition of a saturated solution of NH4Cl and ice. The product was extracted into i-PrOAc and the organics were dried over Na2SO4 and filtered through small pad of silica. Purification of the residue by filtration through a plug of silica (1.5 L) with EtOAc/hexane 10 and 15% yielded 26.92 g (81%) of 17 as a colorless oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[C:10]2[Cl:30].ClC1C2C(=CC=C(C(C3C(C)=NC(C)=CC=3)O)C=2)N=C(OC)C=1CC1C=CC(C(F)(F)F)=CC=1.[CH3:65][N:66]1[C:70]([C:71]([C:73]2[N:77]([CH3:78])[N:76]=[N:75][CH:74]=2)=[O:72])=[CH:69][N:68]=[N:67]1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:30][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:71]([C:70]3[N:66]([CH3:65])[N:67]=[N:68][CH:69]=3)([C:73]3[N:77]([CH3:78])[N:76]=[N:75][CH:74]=3)[OH:72])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1nncc1C(=O)c1cnnn1C
Agent: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
n-BuLi (1.63 M in hexane, 0.139 mL, 0.226 mmol) was added dropwise over 1 minute to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (90.1 mg, 0.209 mmol, Intermediate 12: step d in THF (2.1 mL) at ˜−70° C. under argon. After 2 additional minutes, a homogeneous solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (41.4 mg, 0.215 mmol, Intermediate 13) in THF (2.1 mL) was added dropwise over 1 minute, and the resulting solution was allowed to warm to room temperature overnight as the dry ice/acetone bath expired. The resulting homogeneous yellow reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL), dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=2.02 Hz, 1H), 7.99 (br. s., 1H), 7.91 (d, J=8.59 Hz, 1H), 7.65 (d, J=8.08 Hz, 2H), 7.41-7.51 (m, 3H), 7.19 (s, 2H), 4.36 (s, 2H), 4.04 (s, 3H), 3.84 (s, 6H); MS m/e 544.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=O)C.[OH-].[Na+].Cl>C(O)C>[CH2:15]([O:14][C:12]([C:9]1[C:10]([CH3:11])=[C:6]([CH:4]=[O:3])[NH:7][C:8]=1[CH3:17])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
2,4-Diethoxycarbonyl-3,5-dimethylpyrrole (2.0 g) was dissolved in ethanol (20 ml), and a 1 N sodium hydroxide solution (20 ml) was added and stirred overnight at 80° C. After cooling to room temperature, the reaction mixture was neutralized with a hydrochloric acid solution. The precipitate was collected by filtration, and dried in vacuo. The obtained solid was dissolved in trifluoroacetic acid (20 ml), and stirred for 1 hour at 40° C. While cooling with ice, triethyl orthoformate (2.5 ml) was slowly added dropwise to the reaction mixture. The mixture was allowed to room temperature, and then stirred for 2 hours. The resultant was concentrated at reduced pressure. The residue was added to a saturated sodium hydrogencarbonate and stirred, and then the precipitate was collected by filtration. The obtained solid was purified using medium pressure silica gel flash column chromatography (hexane:ethyl acetate=5:1 to 1:1), and dried in vacuo to afford 5-formyl-2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester (1.21 g, 74%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].[N:30]([O-])=O.[Na+]>O.O1CCOCC1.Cl>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:30]1
Reactant: CNc1cc(-c2ccc(OCc3ccncc3)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4ccncc4)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a suspension of 3-amino-4-(methylamino)-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (580 mg) in water (5 ml) and 1,4-dioxane (5 ml), 2N hydrochloric acid (1.089 ml) was added at 0° C. and sodium nitrite (145 mg) in water (1 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 70 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 410 mg brown solid. Purified by Biotage SNAP cartridge KP-Sil column (25 g, dichloromethane:methanol=1:0, 20:1 to 10:1) then passed through Strata SCX column (20 g) to give 495 mg brown solid as 1-methyl-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (83%).
Reaction SMILES: Cl[C:2]1[N:3]([C:14]2[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:17]([Cl:24])=[CH:16][C:15]=2[F:25])[C:4](=[O:13])[C:5]([F:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH3:26][O-:27].[Na+]>CO>[Cl:24][C:17]1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:14]([N:3]2[C:4](=[O:13])[C:5]([F:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=[C:2]2[O:27][CH3:26])=[C:15]([F:25])[CH:16]=1
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 2-chloro-1-(4-chloro-2-fluoro-5 -isopropoxyphenyl)-5-fluoro-4-trifluoromethyl-6(1H)-pyrimidinone and sodium methylate in methanol there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -fluoro-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 144°-146° C.;
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16]C)=[O:15])=[N:5]2.[OH-].[Na+].Cl>CO>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=[O:15])=[N:5]2
Reactant: COC(=O)c1cccc(Oc2ccc3nccn3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(Oc2ccc3nccn3n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of methyl 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoate (1665 mg, 6.18 mmol) in methanol (30 mL) was added 8N aqueous sodium hydroxide solution (3.00 mL), and the mixture was stirred at room temperature for 18 hr and at 80° C. for 8 hr. After the reaction mixture was allowed to cool to room temperature, 6N hydrochloric acid (4.00 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. Water (30 mL) was added to the residue, and the precipitate was collected by filtration and washed with water. The precipitate was suspended in methanol (10 mL) and the suspension was stirred with heating under reflux for 10 min. After the suspension was allowed to cool to room temperature, the precipitate was collected by filtration washed with methanol and dried under reduced pressure to give the title compound (1045 mg, 4.09 mmol, yield 66%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:11][CH:12]=[C:13]([C:19]([O:21]CC)=[O:20])[C:14](OCC)=[O:15])=[N:8][C:7]=2[CH:24]=1.[OH-:25].[Na+]>C(O)C>[SH:10][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][C:7]=1[N:8]1[C:14](=[O:15])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][NH:11][C:9]1=[O:25]
Reactant: CCOC(=O)C(=CNc1nc2cc(OC)ccc2s1)C(=O)OCC
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S)c(-n2c(=O)[nH]cc(C(=O)O)c2=O)c1

Procedure:
Diethyl N-(5methoxybenzthiazole-2-yl)-aminomethylene-malonate is, as described in Example 1A, Variant II, heated in a mixture of 10% aqueous sodium hydroxide solution and ethanol. Without isolating the 1-(2-mercapto-5-methoxyphenyl)-5-carboxypyrimidine-2,6-dione formed as intermediate, the reaction mixture is strongly acidified, 8-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid thereby precipitating out. The precipitate is subsequently stirred for about 1 hour in the acidic medium. After isolation and drying, the product has a melting point of 277°-278° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:4](=[O:33])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[N:47]=1.CCOCC.CCOC(C)=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:58]([O:57][C:55]([N:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([CH2:45][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[C:4]2=[O:33])=[N:47]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccsc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccsc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 106.3 %

Procedure:
To a stirring solution of 340 mg (0.80 mmol) of 2-(2,4-dioxo-5-thiophen-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, in 10 mL DMF at 0° C. is added 1.93 mL (0.96 mmol, 1.2 equiv) of NaN(TMS)2 in toluene. The resulting solution is stirred 5 min and 299 mg (0.96 mmol, 1.2 equiv) of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is added. The resulting solution is stirred 4.5 h, poured into 100 mL Et2O/EtOAc (1:1), washed with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo to afford 590 mg of the crude title compound: low resolution MS (FAB) m/e 694 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[CH:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CO.[C].[Pd]>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCC=C1CCc2ccc3nc(C)oc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
N-[2-(2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]acetamide (165 mg, 0.644 mmol) was dissolved in methanol (6.4 mL), a 10% palladium-carbon powder (82 mg) was added, and the mixture was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (148 mg, yield 89%).
Reaction SMILES: C([O-])(O)=O.[Na+].[Cl:6][C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:6][C:7]1[N:8]=[N:9][C:10]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)nn2)CC1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
Saturated aqueous NaHCO3 solution (10 mL) was added to a stirred solution of 3,6-dichloropyridazine (0.968 g, 6.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.010 g, 6.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.376 g, 0.33 mmol) in DME (20 mL). The vessel was flushed with nitrogen and the initial suspension was heated at 80° C. for 9 hours. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by MPLC silica chromatography, elution gradient 35 to 45% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(6-chloropyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.929 g, 48.3%) as a colourless crystalline solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][Cl:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:28])[CH2:22][N:23]3[CH2:27]CC[CH2:24]3)[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1.Cl.ClCCN(CCCl)C1C=CC(NC(=O)NC2C=C(NC(=O)CCl)C=CC=2)=CC=1.N1CCCC1>C1COCC1>[ClH:1].[Cl:1][CH2:2][CH2:3][N:4]([CH2:30][CH2:31][Cl:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:28])[CH2:22][N:23]([CH3:27])[CH3:24])[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1
Reactant: O=C(CN1CCCC1)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Agent: Cl
Agent: O=C(CCl)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CN(C)CC(=O)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1

Procedure:
By following the same procedure as that for BO-2189, N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)-phenyl)-2-(pyrrolidin-1-yl)acetamide (BO-2151) hydrochloride was prepared from N-(3-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-2-chloroacetamide (2.2 g, 5.0 mmol) and pyrrolidine (1.6 g, 20 mmol) in THF (50 mL), 1.6 g (69%), mp 66-68° C. 1H NMR (DMSO-d6) δ: 1.90-1.93 (2H, m, CH2), 1.98-2.01 (2H, m, CH2), 3.11-3.15 (2H, m, CH2), 3.61-3.64 (2H, m, CH2), 3.66-3.72 (8H, m, CH2), 6.72-6.74 (2H, d, J=7.8 Hz, Ar—H), 7.19-7.22 (2H, d, J=7.6 Hz, Ar—H), 7.29-7.32 (3H, m, Ar—H), 7.78 (1H, s, Ar—H), 9.04 (1H, brs, NH), 9.31 (1H, brs, NH), 10.35 (1H, brs, NH). 13C NMR (CDCl3, 125 MHz) δ: 22.82, 41.05, 52.88, 54.04, 55.72, 108.81, 112.53, 113.50, 120.03, 129.05, 138.43, 140.72, 152.87, 163.35. HRMS [ES+]: calcd for C23H29Cl2N5O2, 478.4147 [M+H]+. found 478.1777. HPLC 98.6%.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[C:5]2[C@@H:4]2[CH2:20][CH2:21][N:3]12.[Cl:22][CH2:23][C:24](=N)OCC>CN(C)C=O.C(O)C>[Cl:22][CH2:23][C:24]1[O:17][C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:21][CH2:20][C@H:4]4[C:5]=23)=[N:18][N:19]=1
Reactant: CCOC(=N)CCl
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Yield: 54.1 %

Procedure:
A solution of 5 g (17.64 mmol) of (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid hydrazide and 3.06 g (19.41 mmol) of ethyl chloroacetimidate in 40 ml of dimethylformamide and 10 ml of ethanol was stirred at 90° for 12 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and water. The aqueous phase was back-washed once with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol 93:3) yielded 3.26 g (55%) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colourless foam, RF=0.5 (methylene chloride/methanol 10:1).
Reaction SMILES: N[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[I-:16].[Cs+].N(OCCC(C)C)=O>C(Cl)Cl.[Cu]I>[I:16][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: ClCCl
Product: O=c1[nH]c2cc(C(F)(F)F)cc(I)c2[nH]1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(Analogous to the procedure described in Heterocycles, 2001, 55, 461-464). To a solution of 4-amino-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one from step (a) above (0.76 g, 3.5 mmol) in 20 mL of DCM was added CsI (0.91 g, 3.5 mmol), 12 (0.44 g, 1.75 mmol), and CuI (0.2 g, 1.06 mmol). To the mixture was added isoamyl nitrite (2.8 mL, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 3 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with EcOAc (60 mL). The solution was washed with 25% NH4OH (2×30 mL), 5% Na2S2O3 (20 mL) and brine, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 329(M+1)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:9]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:11][C:12]=1[C:13](OCC)=[O:14]>O1CCCC1>[CH3:7][C:8]1[N:9]=[C:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[S:11][C:12]=1[CH2:13][OH:14]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a well stirred solution of lithium aluminium hydride (1.52 g) in dry tetrahydrofuran (50 ml) at 0° C., was slowly added a solution of ethyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazole-5-carboxylate (12.6 g) in dry tetrahydrofuran (50 ml). The mixture was stirred at room temperature for 2 hours. The reaction was quenched by slow addition at 0° C. of water (2 ml), 5N NaOH (2 ml) and water (6 ml). The precipitate was filtered, washed with ethyl acetate, methanol, dichloromethane and tetrahydrofuran. After evaporation, a yellow solid was obtained, that was crystallized from methanol-water to afford the title compound as a yellow solid.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[C:8]([C:10]1[C:15]2[N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[O:18][C:14]=2[C:13]([F:22])=[C:12]([NH:23][C:24](=O)OC(C)(C)C)[C:11]=1[CH3:31])#[N:9].C=O.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[CH3:2][N:23]([CH3:24])[C:12]1[C:13]([F:22])=[C:14]2[O:18][C:17]([CH:19]3[CH2:20][CH2:21]3)=[N:16][C:15]2=[C:10]([C:8]#[N:9])[C:11]=1[CH3:31]
Reactant: Cc1c(NC(=O)OC(C)(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(N(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Trifluoroacetic acid (5 ml) was added to tert-butyl (4-cyano-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazol-6-yl)carbamate (I-318) (70 mg, 0.211 mmol), followed by stirring at room temperature for 1 hour. The reaction liquid was evaporated under reduced pressure, and the resulting residue was dissolved in acetic acid (2 ml). 38% formaldehyde (153 μl, 2.11 mmol) was added to the solution, then sodium cyanoborohydride (70 mg, 2.11 mmol) was added, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction liquid, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (eluent, ethyl acetate:n-hexane=3:1, v/v) to obtain the entitled compound (23 mg, 42%) as a white crystal.