Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cccc(F)c1
Reactant: Brc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Fc1cccc(Nc2ccccc2)c1
Temperature: 105 °C
Yield: 0.1 %

Procedure:
In a 3 liter, three-neck flask equipped with mechanical stirring, a solution of 3-fluoroaniline (75 g, 675 mol), bromobenzene (73 mL, 690 mol), and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (15 g, 18 mmol) in anhydrous toluene (1.3 L) containing sodium tert-butoxide (130 g, 1.35 mol) was heated at 105° C. for 3 h. The reaction mixture was then cooled to 80° C., and then quenched by gradually pouring the reaction mixture into ice water (1 L). The aqueous layer was removed, and was then extracted with an additional volume of toluene (300 mL). The organic extracts were combined, rinsed with brine, dried over MgSO4, and passed through a silica plug (1.3 kg), eluting with toluene. The solvent was removed to give a dark amber oil (86 g). LCMS m/z (%)=188.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 6.45 (t, J=8.5 Hz, 1H), 6.62-6.66 (m, 2H), 6.87 (t, J=7.2 Hz, 1H), 6.98 (d, J=7.6 Hz, 2H), 7.05 (q, J=7.5 Hz, 1H), 7.17 (t, J=8.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([NH2:10])[CH2:8][O:7][CH2:6]1)=[O:4].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([NH:10][S:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([CH3:12])[CH:22]=3)=[CH:26][CH:27]=2)(=[O:32])=[O:33])[CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1COCC1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1COCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
To a slurry of 2.0 g (13.77 mmol) of 4-amino-tetrahydro-furan-3-carboxylic acid methyl ester [WO 01/70673, Examples 46, 58] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (5.13 g, 15.15 mmol) in CH2Cl2 (20 mL) was added saturated aqueous NaHCO3 (20 mL) at 0° C. The solution was allowed to warm to 25° C. over 19 h. The reaction was then diluted with CH2Cl2 (100 mL) and water (30 mL). The organic layer was washed with water (2×50 mL)and then dried over MgSO4, filtered and concentrated to obtain a crude oil (5.13 g ). The crude product was purified by Biotage Flash 40M chromatography, eluting with 1:1 ethyl acetate-hexanes, to afford 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid methyl ester as a white solid (2.3 g, 38%). MS: 457 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=[O:7])[CH3:2].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1.[OH-].[K+]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1ccc(I)cc1F
Reactant: ClCc1ccncn1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(Cc1ccncn1)C(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
N-(2-Fluoro-4-iodo-phenyl)-malonamic acid ethyl ester (20.5 g, 58.4 mmol), 4-chloromethyl-pyrimidine (5.0 g, 38.9 mmol) and potassium hydroxide (3.28 g, 58.4 mmol) were dissolved in IMS (200 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10-40% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (6.9 g, 39%). LCMS (Method B): RT=3.29 min, M+H+=444.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(OCCBr)cc1
Reactant: NCCO
Product: N#Cc1ccc(OCCNCCO)cc1
Temperature: 120 °C

Procedure:
4-(2-Bromoethoxy)benzonitrile (30 g, 0.133 mol; see step (i) above) and ethanolamine (48 mL, 0.78 mol) were mixed and refluxed, under a nitrogen atmosphere, at about 120° C. for 3 h. The reaction was quenched by addition of a sodium hydroxide solution to the mixture. The sub-title compound was extracted using DCM (2×250 mL), which was dried over anhydrous sodium sulfate and then concentrated. Yield: 13.1 g (48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: OB(O)c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a 20 mL press resistant vial which contained a suspension of (R)-2-[4-(4-iodo-benzyl)phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.4 mmol), pyridine-4-boronic acid (110 mg, 0.8 mmol), palladium(II) acetate (10 mg, 0.05 mmol) and triphenyl phosphine (30 mg, 0.1 mmol) in DME (5 mL) was added potassium carbonate (100 mg, 0.7 mmol), ethanol (0.05 mL) and water (0.05 mL) at rt. The tube was sealed and the mixture was allowed to warm to rt and stir at rt for 30 min and then was heated to 98° C. and stirred at 98° C. for 16 h. After cooled to rt, the mixture was poured onto 200 mL ice-water solution and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (20 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (100 mg, 60%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.79-2.08 (m, 4H), 3.27-3.44 (m, 2H), 3.70-3.96 (m, 1H), 3.97 (s, 2H), 4.04-4.20 (m, 2H), 6.82-6.86 (m, 2H), 7.11 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 8.63 (d, J=6.0 Hz, 2H):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCCC1.O>CC(O)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22](=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(=C2C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A suspension of 6-chlorooxindole (1.68 g, 10 mmol) (Cresent Chem.), 1-BOC-4-piperidone (2.20 g, 11.0 mmol) (Fluka), and piperidine (85 mg, 1 mmol) (Aldrich) in 2-propanol (30 mL) was heated at 100° C. for 2 days. Hot water (30 mL) was added to the hot reaction mixture and mixture allowed to cool to room temperature. After standing in refrigerator for 2 hours, crystalline material was collected and washed with cold aqueous methanol to give 4-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-piperidine-1-carboxylic acid tert-butyl ester as a yellow crystalline material. (Yield 2.88 g, 82.4%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[I:17]I.N(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[I:17][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)c(OC)c([N+](=O)[O-])c1
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(I)c(OC)c([N+](=O)[O-])c1
Yield: 96.6 %

Procedure:
To a solution of methyl 3-amino-4-(methyloxy)-5-nitrobenzoate (D163) (370 mg, 1.64 mmol, 1 equiv) in toluene (20 ml) at 0° C. was added iodine (218 mg, 0.86 mmol, 0.5 equiv) then 1,1-dimethylethyl nitrite (200 mg, 1.75 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature for 15 h then partitioned between AcOEt and brine. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel gave methyl 3-iodo-4-(methyloxy)-5-nitrobenzoate (D165) (280 mg, 51%) as a light brown solid. No molecular ion. RT=3.33 min.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50]([O:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62]I)=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:62][C:61]2[CH:64]=[CH:65][C:58]([O:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:59][CH:60]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Reactant: ICc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one (Example 46 c)) dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -70° C. with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (60 min) with 1.946 g (6.0 mmol) of p-benzyloxybenzyl iodide (Example 44a)) in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 4:1) and crystallisation from ethyl acetate/hexane yields the pure title compound: TLC Rf (D)=0.45; tRet (I)=19.9 min; FAB-MS (M+H)+ =608.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2=[O:11].C(N(C(C)C)CC)(C)C.[CH2:39]([O:46][CH2:47][C:48](Cl)=[O:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:46][CH2:47][C:48]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:29])[N:5]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:6]2=[O:11])=[O:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)COCc4ccccc4)c3C2=O)ccc1OC
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of (1S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-isoindole-1,3-dione (1.0 g, 2.4 mmol) in methylene chloride (20 mL), was added diisopropyl ethylamine (0.45 mL, 2.6 mmol), followed by benzyloxy-acetyl chloride (0.37 mL, 2.4 mmol) at 0° C. After 1 hour, the mixture was allowed to warm to 20-25° C. After 15 minutes, the mixture was cooled back to 0° C. To the cooled mixture, was added diisopropyl ethylamine (0.18 mL), and benzyloxy-acetyl chloride (0.14 mL). After 2 hours, the mixture was concentrated, and the resulting residue was purified by Silica Gel column chromatograph to give (1S) 2-benzyloxy-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (1.2 g, 88% yield).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH:37]([CH3:40])[O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH:37]([CH3:40])[O:36]2)=[O:34])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: CC1CCC(C(=O)CBr)O1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2CCC(C)O2)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
Toluene-4-sulphonic acid (3.42g, 17.98mmol) in water (8ml) was added to a solution of 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (4.12g, 10.0mmol) in dichloromethane (20ml) and acetone (20ml). After stirring for 2.5h at room temperature, the reaction mixture was diluted with dichloromethane, washed with water (x2), dried and concentrated in vacuo to yield crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate as a colourless foam. The crude thiol was dissolved in acetone (50ml) and treated with a solution of 2-bromoacetyl-5-methyltetrahydrofuran (1.67g, 8.1mmol) in acetone (5ml). After 10 min., potassium carbonate (687mg, 5.0mmol) was added, and the mixture stirred for a further 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with water (x2) and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane to yield the title compound as a colourless foam (2.68g, 60%); vmax (CH2Cl2) 3412, 1781, 1744, 1685 and 1515cm-1. (Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)].
Reaction SMILES: [CH3:1][C@@:2]([S:42]([CH3:45])(=[O:44])=[O:43])([CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH:30]3[CH2:33][CH:32]([O:34]C4CCCCO4)[CH2:31]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:41])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>O1CCOCC1.CO.CCOCC>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH:30]3[CH2:33][CH:32]([OH:34])[CH2:31]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:41]
Reactant: C[C@@](CCn1ccc(-c2ccc(OCCC3CC(OC4CCCCO4)C3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(OCCC3CC(O)C3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy}phenyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (386 mg, 0.597 mmol) was added 4 N hydrogen chloride in dioxane (6.0 mL) and methanol (0.60 mL). The reaction was stirred for 30 minutes and then evaporated in vacuo to give a yellow oil. The residue was dissolved in a minimal amount of methanol (0.50 mL) and diluted with ether to give a yellow precipitate. This suspension was stirred overnight at room temperature. The solid was allowed to settle and the liquid was decanted off. The solid was rinsed twice with ether and dried on a vacuum pump to give the title compound as a white solid (229 mg, 80.5%). 1H NMR (poor resolution in spectra) (400 MHz, METHANOL-d4) δ ppm 1.55-1.63 (m, 2H) 1.69-1.73 (m, 3H) 1.87-1.97 (m, 3H) 2.11 (t, J=6.83 Hz, 0H) 2.36-2.50 (m, 3H) 2.61-2.72 (m, 1H) 3.08-3.11 (m, 3H) 3.99-4.10 (m, 4H) 4.32-4.42 (m, 1H) 6.89-6.97 (m, 1H) 7.00-7.07 (m, 3H) 7.67-7.73 (m, 2H) 7.87 (t, J=10.54 Hz, 1H). LCMS 479.6 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(C)c2)no1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(N)c(C)c2)no1
Temperature: 80 °C
Yield: 81 %

Procedure:
Ethyl 3-(3-methyl-4-nitrophenyl)isoxazole-5-carboxylate (1.0 equiv.), iron powder (2.0 equiv.), and ammonium chloride (3.0 equiv.) in a mixture of ethanol, tetrahydrofuran and water (4:2:1) were heated to 80° C. for 9 hours. Reaction mixture was cooled and filtered through celite. The filtrate was evaporated to dryness under vacuum and the residue was diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0-2% acetone in chloroform, to provide the title compound as a pale green solid (81%); 1H NMR (300 MHz, DMSO-d6) δ: 1.28-1.33 (t, J=7.2 Hz, 3H), 2.07 (s, 3H), 4.31-4.38 (q, 2H), 5.38 (s, 2H), 6.62-6.65 (d, J=8.4 Hz, 1H), 7.45-7.48 (dd, J=8.1 Hz, 1.8 Hz, 1H), 7.52 (s, 1H), 7.63 (s, 1H); IR (KBr) 3490, 3381, 3135, 2975, 2905, 1725, 1628, 1606, 1471, 1417, 1381, 1279, 1134, 1027, 924, 828, 769 cm−1.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].[CH:8]1([C:11]2[N:15]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:14]=[CH:13][C:12]=2[C:26](Cl)=[O:27])[CH2:10][CH2:9]1>O1CCCC1>[CH:8]1([C:11]2[N:15]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:14]=[CH:13][C:12]=2[C:26]([NH:4][C:3]([NH2:5])=[NH:2])=[O:27])[CH2:10][CH2:9]1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cnn(-c2cccc3ncccc23)c1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
combining guanidine hydrochloride and sodium hydroxide with a suspension of 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid chloride in tetrahydrofuran at a temperature of about −10° C. to about 10° C. for about 1 hour to about 3 hours to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carbonyl)-guanidine; and
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:30][OH:31])[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[C:23](=[O:24])[N:22]3[CH2:25][CH2:26][CH2:27][CH2:28][C:21]3=[N:20][C:19]=2[CH3:29])[CH2:12][CH2:11]1.[OH-].[K+]>O>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[C:23](=[O:24])[N:22]5[CH2:25][CH2:26][CH2:27][CH2:28][C:21]5=[N:20][C:19]=4[CH3:29])[CH2:12][CH2:11]3)=[N:30][O:31][C:2]=2[CH:7]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A solution of 1 g (0.0023 mole) of 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 1 g of potassium hydroxide in 10 ml of water is heated to boiling for an hour. The reaction mixture is cooled to room temperature and extracted twice with 10 ml of dichloromethane each. The organic phase is evaporated. Thus 0.70 g of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimid-in-4-one are obtained, yield 73.5%. According to HPLC analysis the purity of the product is 96.4%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: COc1cccc(Br)n1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)n1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-6-methoxypyridine (290 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (426 mg, 79%) as a light yellow oily substance.
Reaction SMILES: C(Cl)CCl.[N:5]1[C:14]2[NH:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:6]=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][NH:31][CH3:32].C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC>CN(C=O)C>[CH3:32][N:31]([CH2:30][C:22]1[N:21]([CH3:20])[C:29]2[C:24]([CH:23]=1)=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17](=[O:19])/[CH:16]=[CH:15]/[C:7]1[CH:6]=[N:5][C:14]2[NH:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCCN2
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CCCN2
Yield: 70 %

Procedure:
EDC (203 mg, 1.06 mmole) was added to a solution (E)-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (180 mg, 0.88 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (185 mg, 1.06 mmole), HOBt.H2O (143 mg, 1.06 mmole), and Et3N (0.31 mL, 2.2 mmole) in dry DMF (5 mL) at RT. After 18 hr the mixture was concentrated. Flash chromatography on silica gel (10% EtOH/EtOAc) gave the title compound (222 mg, 70%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.99-6.82 (m, 8H), 6.40 (s, 1H), 4.82 (s, 2H), 3.67 (m, 2H), 3.29 (m, 3H), 3.07 (m, 3H), 2.73 (m, 2H), 1.77 (m, 2H); for minor rotomer δ 6.16 (s, 1H), 5.00 (s, 2H); MS (ES) m/e 361 (M+H)+.