Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Cl.CO[N:5]=[CH:6][C:7]1[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]([OH:17])=[CH:9][CH:8]=1>CO>[C:6]([C:7]1[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]([OH:17])=[CH:9][CH:8]=1)(=[NH:5])[NH2:1]
Reactant: CON=Cc1ccc(O)c(C(=O)OC)c1
Reactant: N
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(C(=N)N)ccc1O
Yield: 53.1 %

Procedure:
To a solution prepared by introducing 6.0 g of dried gaseous ammonia into 200 ml of anhydrous methanol, was added with stirring at room temperature 40.0 g of methyl 5-methoxyiminomethylsalicylate hydrochloride. The crystals dissolved, yielding a clear yellow solution and after 5 to 10 minutes there occurred precipitation of colorless crystals. The crystals were collected by filtration and washed with methanol to obtain 16.8 g of methyl 5-amidinosalicylate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])(=[O:19])=[O:18]
Reactant: CCCC(O)CCC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in 35 mL of CH2Cl2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute. The mixture was stirred at 0° C. for 30 minutes, then extracted with H2O (1×15 mL), 5% NH4OH (2×15 mL), 1M HCl (2×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated to an oil. Yield 1.31 g (94%). 1H NMR (300 MHz, CDCl3) d 0.96 (t, 6, J=9), 1.43 (m, 4), 1.64 (m, 4), 3.00 (s, 3), 4.73 (quintet, 1 J=5).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[N:13]=[CH:12][N:11]=1.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:43])[F:42])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)[N:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:42])[F:43])[CH2:29][CH2:30]1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cncnc2)ncn1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cncnc2)ncn1
Reaction time: 17 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[6-(5-pyrimidinyl)pyrimidin-4-ylamino]aniline (Reference Example 21) and 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) were used, and that the reaction was conducted at room temperature for 17 hours and the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: C([N:6]1[CH2:11][CH:10]([CH3:12])[CH:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[CH:8]([CH3:17])[CH2:7]1)(OCC)=O.[OH-].[Na+]>C(O)C>[CH:14]1([NH:13][CH:9]2[CH:8]([CH3:17])[CH2:7][NH:6][CH2:11][CH:10]2[CH3:12])[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CC(C)C(NC2CC2)C(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CNCC(C)C1NC1CC1

Procedure:
The Mixture B of isomers of 1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine (2.8 g, 1.16 mmol) was stirred in a mixture 5 N NaOH solution (20 ml) and ethyl alcohol (5ml) at 100° C. for 120 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford Mixture B of isomers of 4-cyclopropylamino-3,5-dimethylpiperidine as an oil. Yield 1.6 g (84%), C10H20N2, m/z 169 (M+1) PMR (CDCl3): 0.82-1.05 (m, 10H), 1.5 (m, H), 1.75 (m, H,), 2.16-2.38 (m, 3H), 2.65 (m, 1H), 2.78 (m, 1H), 3.02 (m, 1H), 3.41 (m, 1H), 3.64 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCO.C[O-].[Na+]>CO.[Pd]>[CH3:13][O:12][C:10]1[C:9]([O:14][CH3:15])=[C:8]2[C:3]([CH2:4][CH2:5][NH:6][CH:7]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:2][CH:11]=1
Reactant: COc1cc(Br)c2c(c1OC)C(c1ccccc1)=NCC2
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1ccc2c(c1OC)C(c1ccccc1)NCC2
Yield: 100 %

Procedure:
A solution of 5-bromo-7,8-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (450 mg), EtOH (30 mL), 10% palladium-supported carbon (80 mg) and 28% sodium methoxide in MeOH (0.1 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The insoluble materials were subjected to filtration and the filtrate was concentrated to obtain 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[CH2:2][CH2:3][CH3:4].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+]([O-])=O)[C:17]=1[C:18]#[N:19])([O-:15])=[O:14]>>[CH2:1]([NH:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[C:17]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCCCNC(=O)C(C)(C)CO
Product: CCCCNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 215c from N-butyl-3-hydroxy-2,2-dimethylpropanamide (Example 228c) and 2,6-dinitrobenzonitrile in 66% yield. MS 320 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][O:36][CH3:37])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: COCOCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCOCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 486 mg (1.58 mmol) of 5-(benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 281 mg (1.05 mmol) of 1-bromo-9-(methoxymethoxy)nonane in 10 mL of anhydrous THF was added 987 μL (1.58 mmol) of a 1.6 M solution of n-BuLi in pentane. The reaction mixture was stirred under argon atmosphere at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 50 mL of water. The mixture was then extracted with two 50-mL portions of ethyl acetate. The combined organic layer was washed with 80 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×3 cm). Elution with 5:1 hexanes-ethyl acetate afforded the expected product as a light yellow oil: yield 289 mg (56%); silica gel TLC Rf 0.55 (5:1 hexanes-ethyl acetate); 1H NMR (CDCl381.33 (m, 12H), 1.60 (m, 2H), 1.82 (m, 2H), 2.33 (s, 6H), 2.49 (s, 3H), 2.79 (dd, 2H, J=7.6, 7.6 Hz), 3.36 (s, 3H), 3.52 (t, 2H, J=6.4 Hz), 4.62 (s, 2H), 4.90 (s, 2H), 5.87 (s, 2H) and 7.37-7.48 (m, 5H); 13C NMR (CDCl3) δ14.4, 14.4, 19.3, 26.2, 27.7, 29.4, 29.4, 29.5, 29.5, 29.6, 29.8, 31.6, 55.1, 67.9, 75.7, 96.4, 108.0, 108.0, 128.0, 128.58, 128.62, 128.7, 129.3, 136.2, 147.4, 147.4, 152.6, 161.6, 161.6 and 165.1; mass spectrum (APCI), m/z 494.3395 (M+H)1 (C30H44N3O3 requires 494.3383).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:11]1[CH:10]=[C:9]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ccc(Br)cc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
Add copper (I) iodide (109.4 mg, 0.57 mmol), bis(triphenylphosphine)palladium (II) dichloride (365 mg, 0.52 mmol) and triethylamine (5.88 mL, 41.6 mmol), to a solution of 4-bromo-1,2-difluorobenzene (1.17 mL, 10.4 mmol) and trimethylsilylacetylene (1.89 mL, 13.5 mmol), in ethyl acetate (8 mL). Stir at 50° C. for 18h. Cool to room temperature, concentrate and purify the residue by silica gel chromatography, eluting with hexanes, to give the title compound (2.20 g, 100%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]4[C:16](=[O:57])[NH:17][CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][NH:24][C:25](=[O:56])[CH2:26][N:27]([C:54]=3[CH:55]=4)[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[C:41]([NH2:43])[CH:40]=[CH:39][C:38]=3[N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]3)=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]4[C:16](=[O:57])[NH:17][CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][NH:24][C:25](=[O:56])[CH2:26][N:27]([C:54]=3[CH:55]=4)[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[C:41]([NH:43][C:1](=[O:3])[CH3:2])[CH:40]=[CH:39][C:38]=3[N:44]3[CH2:45][CH2:46][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:48][CH2:49]3)=[CH:31][CH:30]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)N1CCN(c2ccc(N)cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(N2CCN(S(C)(=O)=O)CC2)c(COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)c1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
Acetyl chloride (4 μL, 0.057 mmol) was added under nitrogen to a solution of 4 (38 mg, 0.051 mmol) and N,N′-diisopropylethylamine (DIPEA; 8.7 μL, 0.062 mmol) in CHCl3 (2 mL). After 12 h, the reaction mixture was successively partitioned between CHCl3 and diluted NaHCO3, dried (Na2SO4) and evaporated. The residue was purified by column chromatography to give 25 mg (61.7%) of the title product 5 as a white powder: m/z=782 (M+H)+. NMR (DMSO-d6): δ (ppm) 1.19-1.35 (m, 4H), 1.68-1.77 (m, 4H), 1.90 (m, 2H), 2.02 (s, 3H, COCH3), 2.18 (m, 2H), 2.33 (m, 2H), 2.50 (m, 1H), 2.75 (m, 2H), 2.92 (s, 3H, SO2CH3), 2.96 (m, 2H), 3.33 (m, 8H), 4.43 (s, 2H, CH2CONH), 5.22 (s, 2H, OCH2), 5.35 (m, 1H), 5.53 (m, 1H), 7.17-7.20 (m, 3H), 7.39-7.60 (m, 5H), 7.69-7.79 (m, 2H), 7.86 (broad s, 1H, NH), 8.33+8.56 (m, 1H, NH), 9.95 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.[Br:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[S:26][C:27]=1[Cl:28]>>[Br:22][C:23]1[CH:24]=[C:25]([S:29]([NH:21][C:18]2[S:19][CH:20]=[C:16]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=4)=[CH:7][C:2]=3[Cl:1])[N:17]=2)(=[O:31])=[O:30])[S:26][C:27]=1[Cl:28]
Reactant: Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Product: O=S(=O)(Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1)c1cc(Br)c(Cl)s1

Procedure:
The title compound 4-[2-chloro-4-(4 -chlorophenoxy)phenyl]-1,3-thiazol-2-amine (91 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (44.4 mg) with purity >90%: MS (pos) m/z 595.3, 597.3, 599.3; MS (neg) m/z 593.2, 595.2, 597.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:21])=[CH:16][CH:17]=[CH:18]2)=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:15]1[C:14]2[C:19](=[CH:20][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#CCCn1cc2cccc(Cl)c2n1
Reactant: Brc1ccccn1
Product: Clc1cccc2cn(CCC#Cc3ccccn3)nc12
Yield: 19.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (36 mg, 0.23 mmol) and 2-but-3-ynyl-7-chloro-2H-indazole (44 mg, 0.21 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 11 mg (41 μmol, 19%) of 7-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:20][NH:19][C:18]1[CH:17]=[CH:16][C:15]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccc(O)cc2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(O)cc32)cc1
Yield: 30 %

Procedure:
The title compound was prepared from 5-hydroxy-1H-indole-2,3-dione (Ijaz, et al., Indian Journal of Chemistry 1994, 33B, 288-9) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 30% yield: 1H NMR (DMSO-d6): δ6.79 (dd, J=2.2, 8.3 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 6.98 (d, J=2.2 Hz, 1H), 7.25 (s, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 9.20 (s, 1H), 10.80 (s, 1H), 12.82 (s, 1H); APCI−MS m/z 331 (M−H)−.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[N:2].Cl.[NH2:19][OH:20].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:20][NH:19][C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[NH:2]
Reactant: NO
Reactant: N#C[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
Part A. Benzyl (S)-2-cyanopyrrolidine-1-carboxylate (500 mg, 2.17 mmol) was dissolved in aqueous ethanol (3 m-L) and water (1 mL). Hydroxylamine hydrochloride (152 mg, 2.17 mmol) and Na2CO3 (115 mg, 1.08 mmol) were added and the reaction mixture heated to 100° C. for 1 h. The ethanol was removed and the aqueous residue was extracted with dichloromethane (3×25 mL), dried over Na2SO4 decanted and concentrated yielding benzyl (S)-2-(N-hydroxycarbamimidoyl)pyrrolidine-1-carboxylate as a pale yellow gum (428 mg, 75% yield): HPLC (method 1) tR=1.40 min, Purity 76%; LCMS (method 4) tR=0.81 min, m/z 264 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][NH:10][C:11]2=[O:14])=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:17][CH2:16]1)([O-:3])=[O:2].Br[CH2:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][O:34][C:33]3=[O:37])[C:11]2=[O:14])=[CH:6][C:5]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:19][CH2:20]1)([O-:3])=[O:2]
Reactant: O=C1OCCN1CCCBr
Reactant: Cc1ccccc1N1CCN(c2cc3cc[nH]c(=O)c3cc2[N+](=O)[O-])CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cc3ccn(CCCN4CCOC4=O)c(=O)c3cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 7-nitro-6-(4-o-tolyl-piperazin-1-yl)-2H-isoquinolin-1-one (0.25 g, 0.68 mmol) in anhydrous DMF (10 mL), 3-(3-bromo-propyl)-oxazolidin-2-one (0.14 g, 0.68 mmol) was added followed by potassium bis(trimethylsilyl) amide (0.27 g, 1.37 mmol) at 0° C. under N2 atmosphere. The reaction mass allowed to stir at room temperature for 6 h. The progress of the reaction was monitored by LCMS analysis. Upon completion of the reaction, solvent was removed in vacuo. Residue obtained was quenched with water, and extracted in dichloromethane (3×75 mL). The combined extract was washed with water, brine solution and dried over anhydrous Na2SO4. The crude product obtained was purified by the flash column chromatography (230-400 size mesh) using 1.5-1.75% methanol in dichloromethane to afford the compound 7-nitro-2-[3-(2-oxo-oxazolidin-3-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-2H-isoquinolin-1-one. Yield (0.25 g, 75%; and off-color solid).
Reaction SMILES: [N+:1]([N:4]([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].[C:8](Cl)(=[O:10])[CH3:9]>ClCCl>[C:8]([O:6][CH2:5][N:4]([N+:1]([O-:3])=[O:2])[CH3:7])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CN(CO)[N+](=O)[O-]
Solvent: ClCCl
Product: CC(=O)OCN(C)[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred mixture of 10.6 g of 2-nitro-2-azapropanol and 25 ml of dichloromethane under a nitrogen atmosphere was added dropwise and with ice-cooling 12 g of acetyl chloride. The cooling bath was removed and the mixture was slowly heated to reflux. After 3 hours the solution was allowed to cool and was then triturated with 50 ml of ice water. The organic phase was separated, dried (MG SO4), and distilled. The product 2-nitro-2-azapropyl acetate had b.p. 56°-57° C. at 0.07 mm Hg.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)CCC>>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccco2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)furan. The title compound (52 mg) was obtained as a pale solid, m/z 347 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:39])[N:13]2[C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:38].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:39])[N:13]2[C:31]1[C:32]([Cl:38])=[CH:33][CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2c(-c3ccccc3Cl)nc(C3CCNCC3)cc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 mg of tert-butyl 4-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl]piperidine-1-carboxylate in 5 mL of CH2Cl2 was added 2 mL of trifluoroacetic acid. The mixture was stirred at rt for 1 h, then concentrated. The residue was dissolved in 10 mL of CH2Cl2, washed with 5 mL NaHCO3, dried (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH, followed by preparative HPLC (YMC C18 20×50 mm column; 10:90 to 100:0 v/v acetonitrile/water+0.1% TFA over 5 min; 20 mL/min) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:1][O:2][C:3](=[O:8])[CH:4]([NH:5][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH2:6][OH:7]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
To a mixture of 5.0 g (32.14 mmol) of D, L-serine methyl ester and 15.7 mL (0.012 mol) of triethylamine in 100 mL of dichloromethane, cooled to 0° C., was added 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for two days. The mixture was diluted with 100 mL of dichloromethane and then washed with 60 mL each of water, 2N citric acid and brine and than dried over Na2SO4. The solvent was removed under vacuum to give a solid which was recrystallized from ethyl acetate to give 5.0 g (54%) of the product as white crystals, m.p. 92-94° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][CH2:9][C:10]1[CH:40]=[C:39]([F:41])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:12]([F:42])[CH:11]=1.O=C1CCC(=O)N1[O:50][C:51](=O)[CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][NH:78][C:79](=[O:89])[CH2:80][CH2:81][N:82]1[C:86](=[O:87])[CH:85]=[CH:84][C:83]1=[O:88].CCN(C(C)C)C(C)C>>[F:5][C:4]([F:7])([F:6])[C:2]([OH:3])=[O:1].[O:88]=[C:83]1[CH:84]=[CH:85][C:86](=[O:87])[N:82]1[CH2:81][CH2:80][C:79]([NH:78][CH2:77][CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([F:42])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:39]([F:41])[CH:40]=1)=[O:50])=[O:89]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid TFA salt (121 mg, 0.2 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)- propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (100 mg, 0.145 mmol), and DIPEA (258 mg, 348 uL, 2.0 mmol), and after HPLC purification, resulted in a white solid (80 mg, 38%). ES(+)-HRMS m/e calcd. for C50H66F2N6O17 (M+H)+ 1061.4526, obsd. 1061.4521.
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[C:19]1([CH:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[Cl:17][C:12]1[C:11](/[C:2](/[NH:27][CH2:26][CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:28]([CH3:30])[CH3:29])=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Reactant: CC(C)C(CN)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(C#N)=C(\NCC(c1ccccc1)C(C)C)c1cccnc1Cl
Yield: 86.2 %

Procedure:
To a solution of ethyl 3-chloro-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.2 g, 0.738 mmol, 1 eq.) in 3 ml of acetonitril was added 2-phenyl-3-methylbutylamine hydrochloride (0.147 g, 0.738 mmol, 1 eq.) at room temperature followed by triethylamine (TEA) (0.164 g, 1.62 mmol, 2.2 eq.). The reaction was microwaved (130° C., 600 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-2-cyano-3-[(3-methyl-2-phenylbutyl)amino]acrylate (0.253 g, 85% yield) as a mixture of 2 atropoisomers.