Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[F:13][C:14]1([F:31])[CH2:16][CH:15]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=2)[NH2:27])[N:18]=1.CCCP(=O)=O>C(OC(=O)C)C.C(=O)(O)[O-].[Na+]>[F:31][C:14]1([F:13])[CH2:16][C@@H:15]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[C:26]([NH:27][C:10]([C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)=[O:12])[CH:28]=2)[N:18]=1
Reactant: Cc1cc(C)c(-c2noc(C3CC3(F)F)n2)cc1N
Reactant: O=C(O)c1cnc2ccccn12
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2noc([C@H]3CC3(F)F)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 65 °C

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (25 mg, 0.154 mmol) and 5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2,4-dimethylaniline (150) (41 mg, 0.154 mmol) in ethylacetate (1 mL) was added propylphosphonic anhydride solution 50 wt % in ethyl acetate (184 uL, 0.308 mmol). The reaction was heated at 65° C. overnight. The reaction was cooled to room temperature and diluted with a solution of saturated sodium bicarbonate. The organic was separated and washed with water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography and then by a 20×250 mm ChiralPak AD-H column to give (R)—N-(5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2,4-dimethylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F108). 1H NMR (400 MHz, d4-MeOD) δ 10.04 (s, 1H), 9.46-9.44 (m, 1H), 8.57 (s, 1H), 7.95 (s, 1H), 7.79-7.76 (m, 1H), 7.53-7.49 (m, 1H), 7.36 (s, 1H), 7.18-7.15 (m, 1H), 3.74 (m, 1H), 2.55 (s, 3H), 2.47-2.35 (m, 2H), 2.31 (s, 3H). MS m/z 409.14 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1[NH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CCn1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1ncc(NCCc2ccc(OC)cc2)c(Cl)c1=O
Reaction time: 8 h

Procedure:
A mixture comprising 0.5 g of 4,5-dichloro-2-ethyl-3(2H)pyridazinone, 1.18 g of 4-methoxyphenylethylamine, 0.36 g of potassium carbonate, 18 ml of water and 6 ml of 1,4-dioxane, was refluxed under stirring for 8 hours. Then, 1,4-dioxane was distilled off under reduced pressure, and the residue thereby obtained was extracted with ethyl acetate. The extract was washed sequentially with dilute hydrochloric acid and water, and dried over sodium sulfate. Then, solvent was distilled off. The residue was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer, whereby 400 mg of the above identified compound was obtained as colorless crystals having a melting point of from 135° to 135.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:24])[O:10][C:9]=2[C:8]([CH3:25])=[C:7]([OH:26])[CH:6]=1)=[O:4].[C:27]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:24])[O:10][C:9]=2[C:8]([CH3:25])=[C:7]([O:26][CH3:27])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Yield: 84 %

Procedure:
1 mmol of 4-Formyl-3,8-dihydroxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester was dissolved in 3 mL of acetone, 1 mmol K2CO3 was added and stirred for several minutes. Then, 1 mmol of CH3I in acetone was added from a pressure-equalizing dropping funnel. The reaction mixture was monitored by TLC. Upon completion, the reaction mixture was filtered to remove K2CO3 and evaporated by a rotatory evaporator to remove acetone. The residue was purified by column chromatography to give 4-formyl-3-hydroxy-8-methoxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:5].P([O-])([O-])([O-])=[O:12].[Na+].[Na+].[Na+].OO.Cl([O-])=O.[Na+].S(=O)(O)[O-].[Na+]>O.C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]([OH:12])=[O:5]
Reactant: O=P([O-])([O-])[O-]
Reactant: Cc1cccc(Cl)c1C=O
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(Cl)c1C(=O)O
Reaction time: 15 h
Yield: 65 %

Procedure:
A 1000 mL, three-necked, round bottomed flask equipped with a magnetic stirrer, thermometer, addition funnel, and argon inlet was charged with 2-chloro-6-methylbenzaldehyde (71.31 g, 461 mmol, crude obtained from the above experiment) and 750 mL of acetonitrile. To this suspension, a solution of monobasic sodium phosphate (115 mmol, 15.9 g) in water 240 mL) was added followed by hydrogen peroxide (50 mL, 30%) at room temperature. Then, a solution of sodium chlorite (73.5 g, 811 mmol) in water (700 mL) was added dropwise at 0° C. while maintaining the temperature below 3° C. After the addition was complete, the yellow suspension was stirred for 15 h at 0° C. to room temperature. TLC analysis of the mixture indicated the absence of starting material. A solution of sodium bisulfite (73 g, 701 mmol) in water (200 mL) was added dropwise at 0° C. until the yellow color disappeared (KI-paper positive). Cooling was maintained throughout to control the exothermic reaction. The solvent was removed under vacuum to afford a colorless solid. The solid was collected by filtration and the filtrate was extracted with diethyl ether (200 mL). The above solid was dissolved in the combined diethyl ether extracts which were then washed with 10% NaOH solution (2×200 mL). The combined aqueous washings were acidified with 10% HCl to ˜pH 1. The resulting colorless precipitate was collected by filtration and air-dried to afford 54.88 g (65%, overall in two steps) of 2-chloro-6-methylbenzoic acid as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1C(OC(C)(C)C)=O)[C@@H:4]([CH3:25])[C:5]([NH:7][C@@:8]1([C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH3:1][O:2][C@@H:3]([C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C@@H:4]([CH3:25])[C:5]([NH:7][C@@:8]1([C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
617 mg (1.2 mmol) of tert-butyl (2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidine-1-carboxylate (Intermediate 24) were taken up in 44 ml of dichloromethane, 4.4 ml of trifluoroacetic acid were added and the mixture was stirred at RT for 30 min. Subsequently, the reaction mixture was concentrated under reduced pressure and the remaining residue was lyophilized from dioxane/water. 702 mg (quant.) of the deprotected compound (2R,3R)-3-methoxy-2-methyl-N-[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]-3-[(2S)-pyrrolidin-2-yl]propanamide trifluoroacetate were obtained as a crude product, which was used in the following stage without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12
Reactant: Clc1ccnc2cc[nH]c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 170 °C
Yield: 26.1 %

Procedure:
A mixture of 266 (180 mg, 1.18 mmol), 2-fluoro-4-nitrophenol (558 mg, 3.55 mmol) and K2CO3(981 mg, 7.10 mmol) in Ph2O (4 mL) was heated at 170° C. for 8 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography with gradient elution of hexane, to hexane/EtOAc (1:1), to afford the title compound 267 (84 mg, 26% yield) as a yellowish solid. MS (m/z): 274. 1 (M+H) (found).
Reaction SMILES: [NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:33]([O:35]CC)=O)[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5].[NH2:45][NH2:46].O.CN(C=O)C.O>CO>[NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:33]([NH:45][NH2:46])=[O:35])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:5]
Reactant: NN
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CCNC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CCNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 8 h
Yield: 58.7 %

Procedure:
3 Grams of Boc-β-Ala-Ser(Bzl)-Asn-Leu-OEt was dissolved in 20 ml of methanol, then to this solution was added 2.4 ml of NH2NH2.H2O and the mixture was stirred overnight, further 20 ml of DMF was added to the reaction mixture and the precipitate formed was dissolved, and was stirred overnight. The reaction mixture was concentrated under reduced pressure, to the residue thus obtained was added 15 ml of water, and the precipitate formed was collected by filtration and recrystallized twice from ethanol. 1.72 Grams (yield: 58.7%) of the above-mentioned objective product was obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>CO.O.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC(=O)C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A solution of 20.5 g of Z-Asn-Phe-Phe-OH (see case 4-11346, stage 1.5A) in 270 ml of methanol and 30 ml of water is hydrogenated at room temperature on 2 g of palladium-on-carbon (10%) for 4 hours. After filtering off the catalyst, the filtrate is concentrated by evaporation in vacuo and the residue is used directly in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[O:5][CH:6](O)[CH3:7].S(Cl)([Cl:17])=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[O:5][CH2:6][CH2:7][Cl:17]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(OC)c1OC(C)O
Solvent: c1ccncc1
Product: COc1cccc(OC)c1OCCCl
Reaction time: 0.33 h

Procedure:
A solution of 7.77 g of 2,6-dimethoxyphenoxyethanol in 30 ml of pyridine was cooled and 4.7 g of thionylchloride was added with stirring. After 20 minutes, stirring, the reaction mixture was heated on the steam bath for 2 hours. After cooling, the reaction mixture was evaporated in reduced pressure. The residue was extracted with CHCl3, purified with silicagel chromatography (eluent: EtOAc) 1.82 g of objective compound was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[O:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]1>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:16][C@H:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[N:4]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: O[C@H]1CCOC1
Product: BrCc1cccc(CO[C@H]2CCOC2)n1
Yield: 24 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and (S)-tetrahydrofuran-3-ol by the alkylation method described for the final step of Example 32 to give the title compound (24%); NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.5 Hz), 7.39 (1H, d, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 4.67-4.59 (2H, m), 4.52 (2H, s), 4.31-4.26 (1H, m) 3.98-3.81 (4H, m), 2.11-1.99 (2H, m); (M+H)+ 272, 274.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])/[CH:9]=[CH:10]\[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12]>>[CH2:20]([O:19][C:8]([CH:9]([S:1][C:2]1[S:3][C:4]([S:7][CH:9]([C:8]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[N:5][N:6]=1)[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: Sc1nnc(S)s1
Product: CCCCOC(=O)CC(Sc1nnc(SC(CC(=O)OCCCC)C(=O)OCCCC)s1)C(=O)OCCCC
Temperature: 55 °C

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (50.09 g, 0.33 mol) and dibutyl maleate (157.0 g, 0.69 mol) were charged in a reaction flask and heated to 55° C. for 4 hours. The reaction product was filtered warm using filter aid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(O)=[O:16].OO>>[Cl:1][C:2]1[N+:11]([O-:16])=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: OO
Product: COC(=O)c1cc(Cl)c[n+]([O-])c1Cl
Temperature: 70 °C
Yield: 99 %

Procedure:
A solution of methyl 2,5-dichloronicotinate (15 g, 73 mmol), trifluoroacetic acid (91 mL) and 30% aqueous hydrogen peroxide solution (15 mL) were stirred and heated at 70° C. for 1 hour. Evaporation and purification by flash column chromatography using ethyl acetate in hexanes (0-100%) gave the desired product (16 g, 99%). LCMS calculated for C7H6Cl2NO3 (M+H)+: m/z=222.0. found: 221.8.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[NH:26][CH:25]([C:27]([OH:29])=O)[CH2:24][S:23]2)[CH:17]=1.[CH2:30]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].ON1C2C=CC=CC=2N=N1.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58]>C(OCC)(=O)C.C(O)C.CN(C)C=O>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58].[CH2:30]([N:38]1[CH2:39][CH2:40][N:41]([C:27]([CH:25]2[CH2:24][S:23][CH:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[NH:26]2)=[O:29])[CH2:42][CH2:43]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCN1CCNCC1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1
Reaction time: 48 h
Yield: 51.5 %

Procedure:
Dicyclohexylcarbodiimide (0.82 g) was added to a mixture of 0.84 g of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 0.79 g of 1-octylpiperazine, 0.54 g of 1-hydroxybenzotriazole and 20 ml of N,N-dimethylformamide with ice cooling, and the resultant mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. Ethyl acetate was added to the residue, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent 10% methanol-ethyl acetate), the oil obtained was dissolved in 25 ml of ethanol, and 0.32 g of fumaric acid was added. After allowing the mixture to stand for 2 days, the resultant crystals were collected by filtration, washed with cold ethanol and dried. Thus was obtained 0.72 g of 1-octyl-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine fumarate. Melting point 135° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[N:12]3[C:16]([CH2:17][NH:18][CH2:19][C:10]=2[CH:9]=1)=[N:15][N:14]=[C:13]3[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1>>[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[N:12]3[C:16]([CH2:17][N:18]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:19][C:10]=2[CH:9]=1)=[N:15][N:14]=[C:13]3[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Product: O=C(C1CC1)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Yield: 69 %

Procedure:
The title compound was prepared as an off-white foam from cyclopropanecarbonyl chloride and the amine of example 12, in 69% yield, using the procedure described in example 3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C[Mg]Cl.[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][CH2:14][Mg]Br.FC(=C(F)F)CCBr.[Mg]>C1COCC1.CCOCC.S(=O)(=O)(O)O.[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2]>[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCCBr
Reactant: FC(F)=C(F)CC[Mg]Br
Agent: [Cu+2]
Agent: C[Mg]Cl
Agent: FC(F)=C(F)CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CCCCCC(F)=C(F)F
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of 4-bromobutyric acid (8.35 g, 0.05 mole) in anhydrous THF (100 mL) is treated dropwise with methyl magnesium chloride (0.051 mole, 17 mL of 3M solution in THF) at -25° C. with stirring in 15 min. The solution is stirred for an additional 15 min at 0° C. and treated with dilithium tetrachlorocuprate (0.002 mole, 20 mL of 0.1M solution in THF) followed by 3,4,4-trifluoro-3-butenyl magnesium bromide (0.0565 mole, prepared separately from 3,4,4-trifluoro-3-butenyl bromide and magnesium turnings in THF). The mixture is stirred at 0° C. for 2 h and at room temperature for overnight. The solution is then poured in 400 mL of ether and 150 mL of 10% aqueous sulfuric acid. The ether layer is extracted with 10% NaOH (2×50 mL). The aqueous layer is washed with ether, acidified with conc. HCl, and extracted with ether (3×100 mL). The ether extract is dried, concentrated, and the residue distilled under vacuum to give 4.1 g of the desired product as a colorless liquid, a 42% yield. b.p. 125°-127° C./10 Torr.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][C:18]([O:24][CH3:25])([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:27][C:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:24][C:18]1([C:21](=[O:23])[NH:32][C:28]2([CH3:27])[CH2:31][CH2:30][CH2:29]2)[CH2:17][CH2:16][N:15]([CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:20][CH2:19]1
Reactant: COC1(C(=O)O)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1(C(=O)NC2(C)CCC2)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
1-[1-(tert-butoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylic acid (0.163 g, 0.44 mmol) was dissolved in DMF (5 mL) and (1-methyl)cyclobutylamine hydrochloride (0.08 g, 0.66 mmol), HATU (0.25 g, 0.66 mmol) and DIPEA (0.284 g, 0.38 mL, 2.20 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 6% MeOH in DCM]) to give tert-butyl 4-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}azepane-1-carboxylate (0.025 g, 13.4%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]>[Fe].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: NC(=O)c1cc(Cl)ccc1N
Temperature: 90 °C

Procedure:
To 5-chloro-2-nitrobenzamide (2.0 g) (prepared according to the procedure described in Example 1, Part A) was added 50 mL of glacial acetic acid. This solution was heated to 90° C. and iron powder (2.8 g) was added in small portions over 15 minutes. When addition was complete the reaction mixture was stirred at 90°-100° C. After 2 hours the reaction was cooled to room temperature and was evaporated to dryness. The resulting residue was partitioned between ethyl acetate and aqueous sodium carbonate. This brown slurry was filtered and the ethyl acetate layer was recovered and washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield 1.7 g (100%) of a buff powder: 1H NMR (DMSO-d6, 300 MHz) δ 7.83 (bs, 1H), 7.59 (d, 1H), 7.17 (bs, 1H), 7.14 (dd, 1H), 6.70 (m, 3H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].[C:10]1([C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][O:12]1)=[O:11].O>ClC(Cl)C>[CH2:5]([N:7]([CH2:8][CH3:9])[C:10](=[O:11])[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:13][OH:12])[CH3:6]
Reactant: CCNCC
Reactant: O=C1OCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1CO
Reaction time: 0.42 h

Procedure:
To a suspension of aluminium trichloride (12.67 g, 94.98 mmol) in dichloroethane (40 mL) is added diethylamine (13.5 g, 182.7 mmol) in dichloroethane (20 mL) while the temperature is maintained below 25° C. with an ice-bath. After another 25 min at r.t., phthalide (10.00 g, 74.5 mmol) is added in three portions and formation of a precipitate is observed. After 45 min, water and ice are added and the mixture is stirred for 30 min and filtered through celite. The aqueous phase is extracted with dichloromethane. After drying the combined organic phase over MgSO4 and filtering through a cotton plug, the volatiles are removed in vacuo to give an orange residue, which is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1 to 97:3 to 19:1) to give N,N-diethyl-2-hydroxymethyl-benzamide as an orange oil; 1H NMR (400 MHz) δ 1.09 (3 H, t, J=7.0 Hz), 1.28 (3 H, t, J=7.0 Hz), 3.24 (2 H, q, J=7.0 Hz), 3.55 (1 H, t, J=6.8 Hz), 3.58 (2 H, q, J=7.0 Hz), 4.52 (2 H, d, J=6.8 Hz), 7.24 (1 H, dd, J=7.4, 1.5 Hz), 7.32 (1 H, td, J=7.4, 1.5 Hz), 7.39 (1 H, td, J=7.4, 1.5 Hz), 7.44 (1 H, td, J=7.4, 1.5 Hz).