Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[C:3]=1[CH3:24].C1COCC1.[Li]CCCC.Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][C:4]1[C:3]([CH3:24])=[C:2]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[S:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: Brc1nccs1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)c(C)c3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nccs4)c(C)c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 6 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.10 g, 0.25 mmol) and THF (1 mL) is added 1.6 M n-BuLi (0.16 mL). The solution is stirred for 45 minutes and 0.5 M ZnCl2 in THF (0.52 mL, 0.26 mmol) is added. The solution is warmed to ambient temperature and stirred for 30 minutes. 2-Bromo-thiazole (0.044 mL, 0.49 mmol), and PdCl2(dppf) (0.009 g, 0.012 mmol) are added and the solution heated at 65° C. overnight, diluted with EtOAc (25 mL), washed with sat. NH4Cl (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient), furnish the title compound (6.1 mg, 0.015 mmol, 6%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.07 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 2.53 (s, 3H), 3.29-3.39 (m, 1H), 6.68 (s, 1H), 7.35 (d, J=3.1 Hz, 1H), 7.86 (d, J=3.1 Hz, 1H). LC/MS (m/z): calcd. for C22H26N4S2 (M+H)+: 411.6; found: 411.2.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([N:10]2[C:14]3[C:15]4[O:19][CH:18]=[N:17][C:16]=4[C:20]([F:23])=[C:21]([F:22])[C:13]=3[N:12]([C:24]3[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=3[F:31])C2=O)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[K].FC1C2N=COC=2C(NS(C2CC2)(=O)=O)=C(NC2C=CC(I)=CC=2F)C=1F>>[F:23][C:20]1[C:16]2[N:17]=[CH:18][O:19][C:15]=2[C:14]([NH:10][S:7]([C:4]2([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]2)(=[O:9])=[O:8])=[C:13]([NH:12][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])[C:21]=1[F:22]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c(F)c4ncoc4c32)CC1
Agent: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Agent: [K]
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(F)c(F)c3ncoc23)CC1

Procedure:
Compound 1D was prepared from 8-(1-allyl-cyclopropanesulfonyl)-4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-21a: 210 mg, 0.365 mmol) and potassium trimethylsilonolate (50 mg, 0.390 mmol) using procedures analogous to those described above for Compound 1A to afford 150 mg of the product (75% yield). H1NMR (CDCl3, 300 MHz): δ 8.13 (s, 1H), 7.42 (dd, 1H), 7.31-7.25 (m, 1H), 6.80 (s, 1H), 6.43-6.35 (m, 1H), 6.21 (s, 1H), 5.85-5.70 (m, 1H), 5.22-5.14 (m, 2H), 2.83 (d, 2H), 1.28-1.20 (m, 2H), 0.87-0.80 (m, 2H). LCMS: 97.9%, m/z=548.0 (M−1). HPLC: 86.29%.
Reaction SMILES: [CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[NH:5]1)[CH:2]=[CH2:3].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][C:32]=3[F:34])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[NH:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)N1
Yield: 58.9 %

Procedure:
A mixture of (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (188 mg, 0.452 mmol), 2,4-difluorophenylboronic acid (86 mg, 0.581 mmol), Pd(Ph3P)2Cl2 (20 mg) and aqueous Cs2CO3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated at reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-4-allyl-1-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (120 mg, 59%).
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:11]2[C:6](=[CH:7][C:8]([C:21]([O:23]C)=[O:22])=[CH:9][CH:10]=2)[N:5]=1>O.CO>[NH2:3][C:4]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[C:11]2[C:6](=[CH:7][C:8]([C:21]([OH:23])=[O:22])=[CH:9][CH:10]=2)[N:5]=1
Reactant: COC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reaction time: 5 h
Yield: 110.2 %

Procedure:
Lithium hydroxide (29 mg, 1.2 mmol) in water (1 mL) was added to a solution of methyl 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylate (180 mg, 0.60 mmol) in methanol (2 mL) at room temperature. The starting material was consumed after stirring for 5 h, and the reaction mixture was concentrated and dried on lyophilizer to obtain the crude product (190 mg) as an amorphous white solid. (quantitative yield). 1H NMR (300 MHz, DMSO): δ 2.22 (s, 3H), 2.48 (m, 4H), 3.49 (m, 4H), 6.23 (b, 2H), 7.55 (M, 2H), 7.75 (d, 1H); Analytic LCMS (M+H)+: m/z=288.1.
Reaction SMILES: [CH:1]1([C@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:25])[CH2:20][C:21]#[C:22][CH2:23][NH2:24].O>C(Cl)(Cl)Cl>[CH3:18][N:19]([CH3:25])[CH2:20][C:21]#[C:22][CH2:23][NH:24][C:8](=[O:10])[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)[C@@](O)(c1ccccc1)C1CCCCC1
Reactant: CN(C)CC#CCN
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CC#CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of (S)-(+)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid (1.13 g, 80% ee) and N,N'-carbonyldiimidazole (0.77 g) in chloroform (5 ml) was stirred at room temperature for 2 hours. After an addition of 4-dimethylamino-2-butynylamine (0.54 g), the mixture was stirred at the same temperature for an additional hour, then the mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and the organic layer was extracted with 1N-hydrochloric acid. The acidic solution was adjusted to pH 13 with aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with sodium chloride aqueous solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (10:1) as an eluent to give (-)-N-(4-dimethylamino-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.60 g, 88% ee).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[F:9][C:10]([F:18])([F:17])[C:11](C)([CH3:15])[C:12](O)=O.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O>[N+]([O-])([O-])=O.[Ag+]>[F:9][C:10]([F:18])([F:17])[C:11]([C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1)([CH3:15])[CH3:12]
Reactant: N#Cc1cnccn1
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Product: CC(C)(c1cnc(C#N)cn1)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an aqueous (50 mL) solution of 2-cyanopyrazine (6.7 mL), 3,3,3-Trifluoro-2,2-dimethylpropionic acid (10 g) and ammonium peroxodisulfate (22 g) were added, then silver nitrate (16 g) was added, and the resultant was stirred at 80° C. for 8 hours. The reaction solution was subjected to extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→75/25) to obtain the title compound (0.28 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14]Br.O>CC(O)=O>[Br:14][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COc1cc(CC(=O)O)ccc1F
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CC(=O)O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 4-fluoro-3-methoxyphenylacetic acid (5.0 g, 27.1 mmol) in AcOH (20 ml) was added bromine (1.5 ml, 29.8 mmol). The mixture was stirred at room temperature for three hours. Water was added and the precipitate was isolated by filtration. The white solid was washed with water and dried to give (2-bromo-4-fluoro-5-methoxy-phenyl)-acetic acid (6.21 g, 87%).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][NH2:31])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C(Cl)CCl>CN(C=O)C.CCN(C(C)C)C(C)C.C(OCC)(=O)C>[CH2:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29](=[O:32])[CH2:30][NH:31][C:13]([C:9]2[CH:10]=[C:11]([OH:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:15])[CH2:27][CH2:28]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)N1CCN(C(=O)CN)CC1
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.77 g of 1-phenyl-3-carboxy-5-pyrazolone and 3.3 g 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 70 ml DMF 2.7 g HOBT, 5.6 ml DIPEA and 3.4 g EDC were added and the reaction mixture was stirred for 12 h at RT. Then the reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction. Yield: 5.3 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:14][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2)c(N)c1
Yield: 96.1 %

Procedure:
A solution of 44 g (0.21 mol) of 2-nitro-4-methylbiphenyl prepared in Example 1 in 250 ml of ethanol was hydrogenated over 3.0 g of 5% palladium on carbon in a Parr shaker. The uptake of hydrogen stopped after 45 minutes, and the reaction mixture was filtered and concentrated to give 37 g (97%) of 2-amino-4-methylbiphenyl as a brown liquid. This material was distilled through a 15 cm Vigreaux column to give 33 g (87%) of pure 2-amino-4-methylbiphenyl as a colorless liquid, which turned brown on standing.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)nn2)CC1
Yield: 9.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and pyrrolidin-2-one (26 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (11 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccc(Br)cc1
Yield: 72.8 %

Procedure:
A solution of (3-(4-bromophenyl)propionic acid (387 mg, 1.68 mmoles) and benzoic acid N′-isopropyl-hydrazide (300 mg, 1.68 mmoles) in DMF (10 mL) was treated with triethylamine (0.70 mL, 5.05 mmol), HOBT (273 mg, 2.02 mmoles) and EDCI (387 mg, 2.02 mmoles) at room temperature for 72 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated to afford the product as a solid (476 mg, 73%). The product was not further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16](O)(=[O:19])[CH2:17][CH3:18].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]([C:16](=[O:19])[CH2:17][CH3:18])[C:10](=[O:15])[CH2:9]1
Reactant: CCC(=O)O
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CCC(=O)C1C(=O)CC(c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 53.5 %

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (1.0 g), propionic acid (0.60 g) and dimethylaminopyridine (0.82 g) in dimethylformamide (30 ml) was added dicyclohexylcarbodiimide (1.2 g), and the mixture was stirred at room temperature for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethyl acetate. The mixture was washed with 1N hydrochloric acid and water, and to the mixture was added 1N sodium hydroxide solution. The aqueous layer was washed with diethylether, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from diisopropylether and hexane to give colorless crystals of 5-(2-chlorophenyl)-2-propionylcyclohexane-1,3-dione (0.67 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].C(N(CC)CC)C.[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([OH:34])[C:32]4[C:27](=[N:28][CH:29]=[CH:30][N:31]=4)[C:26]3=[O:35])=[N:22]2)=[CH:17][CH:16]=1.C(Cl)Cl>C(#N)C.CN(C)C=O.O.N1C=CC=CC=1>[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([O:34][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[C:32]4[C:27](=[N:28][CH:29]=[CH:30][N:31]=4)[C:26]3=[O:35])=[N:22]2)=[CH:17][CH:16]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 62.4 %

Procedure:
Dimethylcarbamoyl chloride (4.85 g.) and triethylamine (4.55 g.) are added successively to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (4.7 g.) in a mixture of anhydrous methylene chloride (47 cc.) and anhydrous pyridine (16 cc.). The reaction mixture is heated at the reflux temperature for 2 hours, and is then cooled and poured into water (180 cc.). A slight amount of insoluble matter is filtered off and the aqueous layer is decanted off and washed with methylene chloride (2 × 50 cc.) by successive decantations. The combined organic layers are washed by successive decantations with 1N sodium hydroxide solution (2 × 30 cc.) and water (2 × 30 cc.), dried with anhydrous sodium sulphate in the presence of decolourising charcoal, filtered and evaporated to dryness under reduced pressure. The residue obtained is taken up in acetonitrile (20 cc.) and the insoluble product is filtered off and washed with acetonitrile (3 × 2 cc.). Recrystallisation of this product from dimethylformamide (14 cc.) gives a solvated product (4.1 g.). This product is dissolved in dimethylformamide (100 cc.) at a temperature of about 70° C. The solution thus obtained is poured into water (1,200 cc.) and the insoluble product is filtered off and washed with water (5 × 20 cc.). After drying, 6-(7-chloro-1,8-naphthyridin-2-yl)-5-dimethylaminocarbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (3.6 g.), melting at 270° C., is obtained.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][N:14]([CH2:19][C:20]([O:22][C@H:23]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)[CH:35]=3)[CH2:24][C:25]3[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=3[Cl:33])=[O:21])[C:15]2=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C(OCC)(=O)C>Cl>[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][N:14]([CH2:19][C:20]([O:22][C@H:23]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]4[CH2:47][CH2:48]4)[CH:35]=3)[CH2:24][C:25]3[C:26]([Cl:33])=[CH:27][N+:28]([O-:32])=[CH:29][C:30]=3[Cl:31])=[O:21])[C:15]2=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(S)-4-(2-(2-(6-(tert-butoxycarbonylamino)-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (70 mg, 0.099 mmol) was dissolved in HCl 4M in ethyl acetate (1.5 ml, 49.4 mmol). The reaction was stirred at RT for 2 hours. The reaction mixture was concentrated under vacuum, the crude product was triturated with Et2O and filtered to give (S)-4-(2-(2-(6-amino-1-oxoisoindolin-2-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (60 mg, 0.099 mmol, quantitative yield). 1H NMR (400 MHz, acetone) δ ppm 8.33 (s, 2H), 7.68-7.94 (m, 3H), 7.16-7.32 (m, 2H), 7.06 (dd, J=8.19, 1.83 Hz, 1H), 6.93 (t, 1H, CHF2), 6.12-6.23 (m, 1H), 4.61 (s, 2H), 4.46 (d, J=3.18 Hz, 2H), 3.99 (dd, J=6.85, 1.22 Hz, 2H), 3.57 (d, J=9.78 Hz, 1H), 3.37 (d, J=4.65 Hz, 1H), 1.22-1.37 (m, 1H), 0.54-0.68 (m, 2H), 0.40 (d, J=4.65 Hz, 2H); MS/ESI+ 608.42 [MH]+.
Reaction SMILES: [CH2:1]([C:8](=[CH:11]OCC)[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH2:1]([C:8](=[CH:11][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(C#N)Cc1ccccc1
Reactant: C1COCCN1
Product: N#CC(=CN1CCOCC1)Cc1ccccc1
Yield: 40.3 %

Procedure:
9.35 g (0.05 mol) of 2-benzyl-3-ethoxyacrylonitrile and 17.4 g (0.2 mol) of morpholine are refluxed for 20 h. Subsequent vacuum distillation yields 4.6 g of 2-benzyl-3-morpholinoacrylonitrile (81% with respect to the reacted 2-benzyl-3-ethoxyacrylonitrile (50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:17][CH:16]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH:6]([OH:7])[CH2:8][N:23]2[CH2:24][CH2:25][C:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([CH3:14])=[CH:28][CH:27]=3)([OH:26])[CH2:21][CH2:22]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: COc1ccc(CC2CO2)cc1F
Solvent: CO
Product: COc1ccc(CC(O)CN2CCC(O)(Cc3ccc(C)cc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
(RS)-2-(3-Fluoro-4-methoxy-benzyl)-oxirane (0.48 g, 2.6 mmol) and 4-(4-methyl-benzyl)-piperidin-4-ol (0.65 g, 3.2 mmol) were dissolved in MeOH (3 ml) and stirred at room temperature for 16 hours. Solvent was evaporated and residue was chromatographed over silica gel (CH2Cl2MeOH 19:1) to provide (RS)-1-[3-(3-Fluoro-4-methoxy-phenyl)-2-hydroxy-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol (0.82 g, 81%) as a yellow oil MS: m/e=388.5 (M+H+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[O:7][CH:8]=1)(=[O:3])[NH2:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.CO>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:10]2)[O:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1coc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CN(c2nc(C(N)=O)co2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-oxazol-2-yl)-3-hydroxyazetidine (423 mg, 2.31 mmol) (obtained as described in Reference Example 22(2)) in a mixture of methylene chloride (10 ml) and pyridine (30 ml) were added methanesulfonyl chloride (0.90 ml,11.55 mmol) and triethylamine (1.60 ml, 11.55 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, methanol (1 ml) was added to the reaction mixture in an ice bath and then the resulting mixture was stirred at room temperature for 30 minutes. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-(4-carbamoyl-1,3-oxazol-2-yl)-3-methanesulfonyloxyazetidine (470 mg, yield 78%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1C.N1CCCNCC1>>[CH3:10][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:1]=1[N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCCNCC1
Agent: C1CNCCNC1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCNCC1

Procedure:
The title compound was prepared as described in Example 100A, substituting (2-fluoro-5-nitrophenyl)methanol and 1-methyl-1,4-diazepane with 1-fluoro-2-methyl-4-nitrobenzene and 1,4-diazepane (0.7 more equivalent), respectively.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][CH2:25][NH2:26])[O:21][N:20]=1)(=[O:12])=[O:11].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:21][N:20]=1)(=[O:11])=[O:12]
Reactant: NCCc1nc(C2CCCCN2S(=O)(=O)c2nc3ccccc3[nH]2)no1
Reactant: O=Cc1ccccc1
Product: O=S(=O)(c1nc2ccccc2[nH]1)N1CCCCC1c1noc(CCNCc2ccccc2)n1

Procedure:
The title compound was prepared by a similar method to Example 13 from 2-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-yl)ethylamine [see Example 27] and benzaldehyde. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 99:1 changing to 98:2, by volume, dichloromethane:methanol to afford N-(2-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-yl)ethyl)-benzylamine.