Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
Method 1 was followed using 4-fluoro-3-nitrotoluene (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 4-(4-methyl-2-nitrophenyl)piperazine-1-carboxylate (90%). LCMS (m/z): 322.1 (MH+); LC Rt=3.46 min.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH2:19][C:8]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[O:7][N:6]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:4]([C:5]1[CH2:19][C:8]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:9]2)[O:7][N:6]=1)#[CH:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CC(C#C[Si](C)(C)C)=NO2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC1=NOC2(C1)CN(C(=O)OC(C)(C)C)C2

Procedure:
A solution of Compound 28b (557 mg, 1.81 mmol) and tetrabutylammonium fluoride hydrate (759 mg, 2.72 mmol) in 10 mL of THF was stirred at r.t. for 4 h. After the usual work-up with EtOAc-water the crude residue was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CS(C)=O.O>[C:17]([N:24]1[CH2:25][CH2:26][N:27]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a suspension of 1-fluoro-4-nitrobenzene (1.4 mL, 13 mmol) and potassium carbonate (2.5 g, 18 mmol) in DMSO (10 mL) was added 1-Boc-piperazine (2.75 g, 14.8 mmol). The mixture was stirred at 100° C. for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAC/hexanes gave 4.0 g of 1-(4-Boc-piperazin-1-yl)-4-nitrobenzene, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.68 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 3.56 (t, J=5.0 Hz, 4H), 2.96 (t, J=5.0 Hz, 4H), 1.46 (s, 9H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CCCC(=O)O
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 67%), MS (ISP) m/z=401.5 [(M+H)+], mp 191° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and butyric acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=1[N:37]=[C:38]=[O:39].Cl>C1COCC1>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([C:38]([NH:37][C:28]1[C:29]([O:35][CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=1[O:26][CH3:25])=[O:39])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:24]
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)Nc1c(OC)cc(OC)cc1OC)c1ccccc1
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a stirred, room temperature solution of diisopropylamine (43.4 mL, 0.310 mol) in dry THF (1.2 L) was added a 2.5M solution (124 mL, 0.31 mol) of n-butyl lithium in hexanes in one portion, and the mixture was cooled to -78° C. To the solution was added under nitrogen a solution of phenylacetic acid, ethyl ester (50.8 g, 0.309 mol) in THF (500 mL) over 15 minutes. Stirred 2 minutes. To the mixture was added a solution of 2,4,6-trimethoxyphenyl isocyanate (64.9 g, 0.310 mol) in THF (500 mL) over 10 minutes. Stirred 1.5 hours. The reaction was quenched with 1M HCl (310 mL, 0.310 mol) and allowed to warm to room temperature. The mixture was rotoevaporated to remove THF and partitioned between water and chloroform. The organic layer was washed (1M HCl ; saturated NaCl), dried (Na2 SO4), and rotoevaporated. The residue was chromatographed on silica gel (1.4 kg, 230-400 mesh) using petroleum ether-ethyl acetate (1:1). Fractions containing product were rotoevaporated, and the residue crystallized from ethanol-ether to give a white solid; yield 46.9 g (41%); mp 109°-111° C.
Reaction SMILES: [CH2:1]([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].IC>O1CCCC1>[Cl:16][C:17]1[C:25]([Cl:26])=[C:24]([CH3:1])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(Cl)c1Cl
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (23.04 mL, 57.6 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) at −20° C. 2,2,6,6-tetramethylpiperidine (9.72 mL, 57.6 mmol) was added dropwise and stirred for 15 minutes maintaining a temperature of −20° C. The solution was cooled to −78° C. whereupon 2,3-dichlorobenzoic acid (5 g, 26.2 mmol, commercially available from e.g. Sigma-Aldrich, Alfa Aesar or Fluorochem) dissolved in Tetrahydrofuran (THF) (50 mL) was added dropwise. The solution was stirred at −78° C. for 1 hour whereupon iodomethane (6.55 mL, 105 mmol) was added dropwise and the mixture allowed to reach room temperature overnight. Solvents were removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and 5N HCl (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL), combined extracts were washed with water (50 mL), brine (50 mL) dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a crude solid in 5.90 g.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([NH:7][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21])[CH3:8])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of L-alanine ethyl ester hydrochloride (50 g, 325 mmol) in anhydrous dichloromethane (800 mL) added triethylamine (65.8 g, 650 mmol) and stirred at room temperature for 30 minutes. To the reaction mixture cyclopropanecarbonyl chloride (50.96 g, 0.487 mole) was slowly added and stirred at room temperature for overnight. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a mixture of ethyl acetate:hexane (1:1) as eluant to give 2-(cyclopropanecarbonyl-amino)-propionic acid ethyl ester (163) (58.0 g, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Cc1cccc(N)c1C(N)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(C)c4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2.79 g, 8.2 mmol) and 2-amino-6-methylbenzamide (0.830 g, 5.46 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-methylbenzamide was isolated as a yellow solid (0.960 g, 38% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H), 2.36 (s, 3 H), 6.49 (s, 1 H), 7.18-7.24 (m, 2 H), 7.30 (s, 1 H), 7.44-7.47 (m, 4 H), 7.56 (d, J=4.03 Hz, 1 H), 7.95 (d, J=8.43 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(O)(C)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=[C:2]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=1
Reactant: CC(C)(C)Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)CN
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(Cl)nc(NC(C)(C)C)n1

Procedure:
After dissolving 5.0 g of 4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine in 25 ml of isopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane, the reaction mixture is boiled under reflux for 20 hours, then the reaction mixture is evaporated and the residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The residue is recrystallized from hexane to give the title compound in a yield of 4.49 g (73%), m.p.:109.5°-111° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH:9]3[CH:7]([CH:8]3[C:11]([OH:13])=O)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:19][C:20]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([NH:33][NH2:34])=O)=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][O:25]2>>[Cl:30][C:29]1[C:20]([NH2:19])=[C:21]2[C:26](=[C:27]([C:31]3[O:13][C:11]([CH:8]4[CH:7]5[CH:9]4[CH2:10][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:6]5)=[N:34][N:33]=3)[CH:28]=1)[O:25][CH2:24][CH2:23][CH2:22]2
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCCC2
Reactant: O=C(O)C1C2CN(C3CCC3)CC21
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(-c2nnc(C3C4CN(C5CCC5)CC43)o2)c2c1CCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.1 %

Procedure:
To 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylic acid (74 mg, 0.40 mmol, obtained in preparation 8) was added phosphoryl chloride (1 mL). The mixture was stirred for 15 minutes and 5-amino-6-chloro chroman-8-carboxylic acid hydrazide (80 mg, 0.33 mmol) was added. The reaction mixture was gradually heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, triturated with hexanes (2×20 mL) and the crude mass was basified with aqueous sodium bicarbonate solution. The basified mixture was extracted with 10% methanol in dichloromethane The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure and was purified by silica gel column to obtain 6-chloro-8-[5-(3-cyclobutyl-3-aza bicyclo[3.1.0]hex-6-yl)-[1,3,4]oxadiazol-2-yl]chroman-5-yl amine (18 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10]C)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:12][NH2:13]>C(O)C>[NH2:12][NH:13][C:8](=[O:10])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN1CCOCC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCOCC1

Procedure:
To a solution of methyl 2-morpholin-4-ylacetate (1.0 g, 6.28 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.305 mL, 6.28 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a solid in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ8.11 (br s, 1H), 3.87 (br s, 2H), 3.71 (t, 4H), 3.09 (s, 6H), 2.53 (t, 4H); ES-MS (m/z) 160 [M+H]+.
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N+:10]([CH3:16])=[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]=[C:7]2SC.[I-].[CH3:26][C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:8][C:7]2=[CH:26][C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32]
Reactant: COc1cc2c(SC)nc(-c3ccccc3)[n+](C)c2cc1OC
Reactant: Cc1sc2ccccc2[n+]1C
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)N(C)C(c1ccccc1)=NC2=Cc1sc2ccccc2[n+]1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
500 mg (1.10 mmol) 6,7-Dimethoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 320 mg (1.10 mmol) 2,3-Dimethyl-benzothiazol-3-ium iodide were dissolved in 200 ml dimethylformamide and 445 mg (0.61 ml, 4.40 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue is washed with water and methanol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:31]=[CH:30][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:26]C(=O)C)[CH:17]=[C:18]([C:20]5[O:21][C:22]([CH3:25])=[CH:23][CH:24]=5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:31]=[CH:30][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:26][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])[CH:17]=[C:18]([C:20]5[O:21][C:22]([CH3:25])=[CH:23][CH:24]=5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(=O)Nc1cc(-c2ccc(C)o2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: Cc1ccc(-c2cc(NS(=O)(=O)C3CC3)cc(-n3cnc4cc(-c5cnn(C)c5)ccc43)c2)o1

Procedure:
The compound was prepared from the compound of Example 73 using the procedures of Example 74 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, CD3OD): δ 8.5 (s, 1H), 8.0 (s, 1H), 7.95 (s, 1H), 7.9 (s, 1H), 7.6-7.7 (m, 4H), 7.5 (s, 1H), 6.8 (d, 1H), 6.2 (s, 1H), 4.0 (s, 3H), 2.4 (s, 3H), 1.0-1.5 (m, 4H). LC-MS (ESI): Calculated mass: 473.55; Observed mass: 474.0 [M+H]+ (rt: 1.382 min).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>>[Cl:3][CH2:6][C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C(CO)C(=O)OCC
Reactant: O=S(Cl)Cl
Product: C=C(CCl)C(=O)OCC
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Thionyl chloride (10.6 g, 89.1 mmol) was dropwise added to ethyl α-hydroxymethylacrylate (10 g, 76.8 mmol) with ice-cooling; stirring was conducted for 30 minutes; then, a reaction was allowed to take place at 90° C. for 2 hours. After the completion of the reaction, low-boiling compounds were removed under reduced pressure to obtain unpurified ethyl α-chloromethylacrylate (11.8 g). Then, L-arabinoaminooxazoline (11.8 g, 64.0 mmol) was suspended in dimethylacetamide (80 ml). Thereto was dropwise added the ethyl α-chloromethylacrylate (11.8 g) with ice-cooling. A reaction was allowed to take place at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue was added isopropanol (100 ml), and the resulting mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, washed with isopropanol (10 ml), and dried under reduced pressure to obtain a title compound (12.5 g g, 60.5%).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[NH2:22]>CO>[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:23][C:2]([CH3:13])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11][CH3:12])[N:22]=1
Reactant: COC(=O)CCCCC(N)=O
Reactant: COc1ccccc1C(=O)C(C)Br
Solvent: CO
Product: COC(=O)CCCCc1nc(-c2ccccc2OC)c(C)o1

Procedure:
Combine 2-Bromo-1-(2-methoxy-phenyl)-propan-1-one (7.25 g, 29.8 mmol) with 5-carbamoyl-pentanoic acid methyl ester (9.5 g, 60.5 mmol) and heat the neat mixture in a sealed vessel at 140-150° C. for about 4 h. Cool the mixture, transfer to a flask using methanol and concentrate. Partition the residue between water and EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatography over silica gel (MeOH/CH2Cl2) allows for recovery of 5-[4-(2-methoxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid methyl ester (3.63 g, 40%). MS (ES): (M+1)+ 304.2 m/z.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([OH:26])=O)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32](=[O:48])[NH:33][CH2:34][CH2:35][CH2:36][C@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][NH2:39])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C@H:12]([C:24]([NH:39][CH2:38][C@@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:48])=[O:26])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 120 mg (0.33 mmol) of N5-(tert-butoxycarbonyl)-N2-[(benzyloxy)carbonyl]-L-ornithine and 136 mg (0.43 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 6 ml of dimethylformamide with the addition of 82 mg (0.43 mmol) of EDC and 13 mg (0.1 mmol) of HOBt. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).
Reaction SMILES: ClC(Cl)(Cl)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[CH3:14][C:15]1([CH3:28])[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=2)[CH2:18][NH:17][CH2:16]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:14][C:15]1([CH3:28])[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=2)[CH2:18][N:17]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH2:16]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(CC(F)(F)F)Cc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoroethyl trichloromethanesulfonate (1.8 g, 6.40 mmol) was added to a solution of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.8 g, 3.88 mmol) and sodium bicarbonate (0.66 g, 7.86 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at 60° C. for 16 hour. The mixture was concentrated, and CH2Cl2 (70 mL) and water (70 mL) were added to the residue. After separation, the aqueous layer was extracted with CH2Cl2 again. The combined organic layers were washed with saturated aqueous NaCl (1×150 mL), dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:38][C@H:39]1[CH2:43][NH:42][CH2:41][C@@H:40]1[OH:44].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[NH2:38][C@@H:39]1[C@@H:40]([OH:44])[CH2:41][N:42]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([Cl:28])([F:26])[F:27])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:43]1
Reactant: N[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncc(F)c2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 44 h

Procedure:
2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 70 mg, 0.160 mmol) and DIPEA (0.196 mL, 1.121 mmol) were added to a vial containing iPrOH (2 mL). (3S,4S)-4-Aminopyrrolidin-3-ol (30 mg, 0.168 mmol) was added. The mixture was stirred at 80° C. for 44 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced to give the crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/MeOH, from 95:5 to 8:2) to afford the title product as a beige solid. HPLC (Condition 10) tR=5.83 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=494.2/496.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.91 (dd, J=11.53, 2.93 Hz, 1H) 3.22-3.28 (m, 1H) 3.36-3.46 (m, 2H) 3.59-3.66 (m, 1H) 4.02-4.08 (m, 1H) 5.48 (d, J=3.91 Hz, 1H) 7.35 (d, J=8.60 Hz, 2H) 7.87 (m, J=9.00 Hz, 3H) 8.13 (d, J=2.35 Hz, 1H) 8.55 (s, 1H) 8.64 (d, J=2.74 Hz, 1H) 8.79-8.83 (m, 1H) 10.22 (s, 1H).
Reaction SMILES: CON(C)[C:4](=[O:6])[CH3:5].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][Mg]Br>CCOCC>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][C:4]([CH3:5])=[O:6])[CH:15]=[CH:16][CH:17]=1
Reactant: CON(C)C(C)=O
Reactant: Br[Mg]Cc1cccc(Br)c1
Solvent: CCOCC
Product: CC(=O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methylacetamide (10 g, 0.10 mol) in 200 mL of ether at 0° C. was added 3-bromobenzylmagnesium bromide (0.25 M, 200 mL, 50 mmol). After stirring at 0° C. for 2 h, the reaction mixture was partitioned between hexane and saturated aqueous ammonium chloride. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.5-7.1 (m, 4H), 3.78 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:25])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:26]=[S:27]1(=[O:41])[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:41]=[S:27]1(=[O:26])[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:14]4[CH:15]=[C:10]([NH:9][C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH:11]=[CH:12][C:13]=4[Cl:25])=[CH:17][CH:18]=3)=[O:23])=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: O=C(O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reaction time: 18 h
Yield: 21.6 %

Procedure:
A mixture of 5′-(cyclohexanecarbonyl-amino)-2′-chloro-biphenyl-4-carboxylic acid (100 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (67 mg), triethylamine (0.098 ml) and HBTU (159 mg) in dry DMF (5 ml) was stirred at 20 C for 18 h. The mixture was then evaporated to dryness and purified via reversed-phase preparative HPLC (eluting with acetonitrile/water) to afford the title compound as an orange solid (35 mg).