Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([OH:50])=O)=[CH:44][C:43]=2[F:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=1>ClCCl.CCN(C(C)C)C(C)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[O:50])[N:59]([C:56]3[CH:57]=[CH:58][C:53]([Cl:52])=[CH:54][CH:55]=3)[CH3:60])=[CH:44][C:43]=2[F:51])[CH2:34][CH2:33]1)=[O:31])([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(=O)O)cc2F)CC1
Reactant: CNc1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
PyBroP (606 mg, 1.3 mmol) was added to a solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (382 mg, 11.0 mmol) in dichloromethane (20 ml) and DIEA (to pH9). The mixture was stirred for 1 h at room temperature then (4-chloro-phenyl)-methyl amine (156 mg, 1.1 mmol) was added. The mixture was stirred for 2 days at room temperature then solvents were concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (210 mg, 41%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([C:20]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:21])[CH:23]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)N1CCOCC1
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a solution of morpholine (870 mg, 10 mmol) and triethylamine (1.1 g, 10.8 mmol) in CH2Cl2 (15 mL) was added a solution of 5-fluoro-2-methylbenzoyl chloride (1.72 g, 10 mmol) in CH2Cl2 (5 mL), dropwise, and the mixture stirred for 15 min. The mixture was then washed with water, and the organic fraction dried (MgSO4), filtered, and concentrated to obtain 2.19 g (Yield 98%) of the title compound as a solid: 1H NMR (500 MHz, CDCl3) δ ppm: 2.27 (3H, s) 3.24 (2H, d, J=4 Hz) 3.58 (2H, s) 3.79 (4H, dd, J=18, 3.8 Hz) 6.88 (1H, dd, J=8.2, 2.8 Hz) 6.92-7.05 (1H, m) 7.18 (1H, dd, J=8.4, 5.3 Hz).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A mixture of 4.19 g of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine, 1.7 g of (3R)-3-ethynyl-3-quinuclidinol, 500 mg of tetrakis(triphenylphosphine)palladium(0), 10 mg of cuprous iodide, 4.2 ml of triethylamine and 13 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 70° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 5% methanol/ethyl acetate, to give 1.54 g of the target compound.
Reaction SMILES: [O:1]1CCC[CH2:2]1.[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33]Br.CO.C[O-].[Na+]>O>[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33][O:1][CH3:2]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To 4 ml of tetrahydrofuran solution containing 459 mg (0.81 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added 4 ml of 28% sodium methoxide methanol solution, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 359 mg of the title compound as a colorless oil. (Yield: 86%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CCOCC1c1cc(F)cc(F)c1
Reactant: O=C=NC(=O)Cl
Product: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)cc(F)c1)COC2
Temperature: 55 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
The mixture of 3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one (Preparation X2) (800 mg, 3.77 mmol) and carbonisocyanatidic chloride (557 mg, 5.28 mmol) was heated in a sealed bottle at 55° C. for 1 h and then at 130° C. for 2 h. The mixture was cooled to RT. Partition between EtOAc and saturated NaHCO3 solution. Extracted with EtOAc(×3 times). The combined organic layers was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel to give 8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (230 mg, 0.818 mmol, 21.69% yield). LC-MS (M+H)+=282.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.94 (br, s., 1H) 6.85-7.01 (m, 2H) 6.81 (tt, J=8.81, 2.17 Hz, 1H) 4.70 (d, J=15.56 Hz, 1H) 4.49 (dd, J=15.56, 2.14 Hz, 1H) 4.03-4.12 (m, 2H) 3.68 (br. s., 1H)
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[C:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:35][N:36]([CH3:38])[CH:37]=1>CN(C)C=O.O>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:33]2[C:34]([NH:39][C:40]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:46])=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:15][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)c(NC(=O)OC(C)(C)C)n1
Reactant: COC(=O)C(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (353 mg, 0.43 mmol) was added to a degassed, ambient temperature solution of methyl 2-(acetylamino)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.5 g, 4.3 mmol), potassium carbonate (2.39 g, 17.3 mmol) and tert-butyl (4-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (1.19 g, 4.3 mmol) in wet N,N-dimethylformamide (40 mL). After stirring at 85° C. overnight, the reaction mixture was cooled, diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded methyl 2-(acetylamino)-3-(4-{3-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrazo 1-4-yl}phenyl)propanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.[BrH:11].BrBr.O>C(O)(=O)C>[Br:11][CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C(=O)CBr)cc1
Temperature: 30 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a stirring solution of 20 g (150 mmol) of 4-methylacetophenone in 100 mL of glacial acetic acid was added catalytic amount of HBr (0.5 mL) followed by 21.40 g (134 mmol) of bromine dissolved in acetic acid (30 mL) dropwise at 10-15° C. The reaction mixture was stirred at 25-35° C. for 5 hrs, then poured into water (100 mL). The solid that separated was filtered to give the required product (20 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:17][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH2:16])[C:14]=3[S:15][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:4].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CC(O)=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:17][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:16][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:14]=3[S:15][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:4]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N)cccc12
Reactant: O=C1CCCCC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NC3CCCCC3)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Step A Reductive Amination: To a solution of 7-Amino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (250 mg, 0.68 mmol) in DCE (6.5 mL) was added cyclohexanone (0.071 mL, 0.68 mmol), and NaBH3(OAc)3 (250 mg, 1.2 mmol). HOAc (0.05 mL, 0.82 mmol) was then added drop-wise and the solution was allowed to stir at ambient temperature for two hours after which the reaction was judged complete by TLC. The solution was filtered through silica gel, concentrated in vacuo and purified via normal phase SiO2 chromatography using a 0% to 15% ethyl acetate/hexane gradient, affording 180 mg of 7-Cyclohexylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as a viscous yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:29]Br.O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:11](=[O:23])[C:10]=1[Br:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cn2ccc(OCc3ccccc3)cc2=O)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Reaction time: 2 h

Procedure:
The material prepared in Example 1 (2.1 g, 0.007 mol) and sodium acetate (738 mg, 0.009 mol) in glacial acetic acid (15 mL) were cooled to 15° C. Bromine (0.412 mL, 0.008) in glacial acetic acid (5 mL) was added dropwise. Contents were stirred 2 hours, coming to room temperature. Water (200 mL) was added and a light yellow solid was filtered. Mp 150.4-151.2° C. FABHRMS m/z 384.0599 (M+H, C20H19BrNO2 requires 384.0601). 1H NMR (CDCl3/300 MHz) δ: 7.42-7.30 (m, 5H); 7.22-7.08 (m, 5H); 6.02 (d, 1H); 5.20 (s, 2H); 5.12 (s, 2H); 2.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][NH:17][NH2:18].O>CO>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[N:17]([CH3:16])[NH2:18]
Reactant: CNN
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Solvent: CO
Solvent: O
Product: CN(N)c1cnn(-c2ccccc2)c(=O)c1Cl

Procedure:
To a solution consisting of 22.9 grams of 4,5-dichloro-2-phenylpyridazin-3(2H)-one in 120 grams of methanol is added 20 grams of methylhydrazine. The reactants are heated to reflux for two hours, cooled and poured into one kilogram of water. The resulting precipitate is separated by filtration, washed with water and dried. The solid is crystallized from benzene and methanol to yield 4-chloro-2-phenyl-5-(1-methylhydrazino)-pyridazine-3(2H)-one (m.p. 128° to 130° C with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[OH-].[K+].Br[CH2:18][CH2:19][CH3:20]>C(O)CCC>[CH2:18]([O:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH2:19][CH3:20]
Reactant: O=C(O)CCC(=O)c1ccccc1O
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCOc1ccccc1C(=O)CCC(=O)O

Procedure:
3-(o-Hydroxybenzoyl)propionic acid (14.6 g.) was dissolved in n-butanol (300 ml.) containing 85% potassium hydroxide (10 g.) and the resultant solution was treated with 1-bromopropane (24.6 g.) and the mixture heated at reflux temperature for 4 hours. It was then cooled, filtered to remove potassium bromide and the filtrate washed with cold water. The butanol was evaporated at reduced pressure and the residual oil distilled at 0.3 mm when the fraction b.p. 160°-180° C was collected (16.4 g.). This was dissolved in methanol (50 ml.), treated with 20% sodium hydroxide solution (20 ml.) and heated on the steambath for 30 minutes. The methanol was boiled off and the residue diluted with water (250 ml.) and acidified with hydrochloric acid. The precipitated acid was collected and crystallised from 50% methanol. It had m.p. 77°-79° C (Yield 13.3 g.).
Reaction SMILES: [CH:1]1([CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18][C:19]1[C:20](=[O:36])[NH:21][C:22](=[O:35])[N:23]([CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[C:24]=1[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:18][C:19]1[C:20](=[O:36])[N:21]([CH2:8][C@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22](=[O:35])[N:23]([CH2:26][C:27]2[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=2[F:33])[C:24]=1[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(CO)C1CCCCC1
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A solution of tert-butyl 1-cyclohexyl-2-hydroxyethylcarbamate 4a (638 mg, 2.62 mmol) in THF (10 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)-6-methylpyrimidine-2,4(1H,3H)-dione 1d.1 (869 mg, 2.62 mmol) and triphenylphosphine (1.03 g, 3.93 mmol) at ambient temperature, then di-tert-butylazodicarboxylate (906 mg, 3.93 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 16 hours and volatiles were evaporated. The residue was partitioned between saturated NaHCO3/H2O and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 25% EtOAc/hexanes) to give compound 4b (1.39 g, 95.4% ). MS (CI) m/z 456.1, 458.1 (MH+-Boc).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19].N1CCCCC1>C(O)C>[C:18]([C:17]1[C:16](=[NH:20])[O:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:19]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a mixture of 2-hydroxybenzophenone (2.0 g, 10 mmol) and malononitrile (661 mg, 10 mmol) in ethanol (15 mL) was added piperidine (0.5 mL, 5.0 mmol). The mixture was stirred under 0-5° C. for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 1.2 g (48%) of the title compound. 1H NMR (CDCl3): 7.74-7.29 (m, 7H), 7.20-7.13 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@:19]3([CH3:30])[O:23][C:22]4=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]4[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:33]N(C=O)C.[H-].[Na+].CI>O>[CH3:33][N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C@:19]2([CH3:30])[O:23][C:22]3=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]3[CH2:20]2)[CH2:16][CH2:17]1)=[O:11]
Reactant: C[C@]1(CN2CCN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(C(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid (4-trifluoromethylphenyl)amide prepared in Example 477 (200 mg, 0.44 mmol), DMF (4 ml), and sodium hydride (26 mg, 0.66 mmol) was stirred at room temperature for 1.5 hours. To the mixture, methyl iodide (0.5 ml, 0.76 mmol) was added followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid N-methyl-N-(4-trifluoromethylphenyl)amide (35 mg, yield 17%) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25](Br)[N:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2>CN1CCCC1=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)[N:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Brc1cc2cccnc2c(Br)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Br)cc3cccnc23)C1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
To (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.776 g, 4.17 mmol) in N-methyl-2-pyrrolidinone (12 mL) at 0° C. was added NaH (0.139 g, 3.47 mmol). The mixture was stirred for 5 minutes. Next, 6,8-dibromo-1,7-naphthyridine (1 g, 3.47 mmol) was added and the reaction mixture was stirred at RT for 5 minutes and then heated at 135° C. for 30 minutes in a microwave reactor. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified using silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane over a 45 minute period to give the title compound as a yellow solid (1.3 g, 95%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]=[O:46])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]([OH:46])[CH2:17][C:15](=[O:16])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1
Reactant: CC(C)c1sc(-c2ccccc2)c(-c2ccc(F)cc2)c1C=CC=O
Reactant: CCOC(=O)CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a solution of 2.6 g of diisopropylamine in 30 ml of THF at 0° was added 1.67 g of n-butyllithium (1.16 m in hexane). Then a solution of 1.7 g of ethyl acetoacetate in 10 ml of THF was added dropwise. After stirring at 0° for 1 hour, the mixture was cooled to -20°, then a solution of 3.3 g of the title product of Step 3, above, in 20 ml of THF was added dropwise. The reaction was stirred at -20° for 1 hour. Then was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with MTBE and then methylene chloride and the organic solutions were combined and dried, adn the solvent evaporated under reduced pressure to give 5.5 g of crude title product of this step as an oil. This was used without further purification in the next step (Step 5).
Reaction SMILES: [NH2:1][N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=[O:8].[CH3:9][C:10]1([CH3:24])[C:19]2([CH3:21])[O:20][CH:18]2[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:22]#[N:23])[CH:16]=2)[O:11]1>>[CH3:9][C:10]1([CH3:24])[C:19]([CH3:21])([OH:20])[CH:18]([NH:1][N:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=[O:8])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:22]#[N:23])[CH:16]=2)[O:11]1
Reactant: Nn1ccccc1=O
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21C
Product: CC1(C)Oc2ccc(C#N)cc2C(Nn2ccccc2=O)C1(C)O
Reaction time: 8 h

Procedure:
A mixture of 1.1 g of 1-amino-1,2-dihydropyridin-2-one and 3.1 g of 2,2,3-trimethyl-3,4-epoxy-6-cyanochroman is heated to the melting point and stirred at this temperature for 8 hours. The residue is purified by column chromatography (dichloromethane/ethyl acetate; silica gel). 2,2,3-Trimethyl-4-(1,2-dihydro-2-oxo-1-pyridyl-amino)-6-cyano-3-chromanol, m.p. 184°-187°, is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:17](=[O:19])[CH3:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available (S)-1-(3-bromophenyl)ethanamine (1.0 g, 5 mmol) was dissolved in THF (20 mL). Pyridine (0.5 mL) and acetic anhydride (0.51 g, 5 mmol) were added and the reaction mixture allowed to stir at room temperature overnight. The solvent was removed under reduced pressure to provide A4a.1 (1.23 g) as a clear yellowish liquid. (M+H)+=242.15, 244.16.