Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[CH3:8][N:9]1[C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:13]2=[CH:14][CH:15]=[CH:16][N:12]2[CH2:11][CH2:10]1.CN(C)C=O>O1CCCC1>[C:6]([C:16]1[N:12]2[CH2:11][CH2:10][N:9]([CH3:8])[C:17]3([CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[C:13]2=[CH:14][CH:15]=1)#[N:5]
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
A solution of chlorosulfonyl isocyanate (590.9 mg, 363.4 μL, 4.175 mmol) in tetrahydrofuran (2 mL) was slowly added to a solution of tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1020 mg, 3.340 mmol) in tetrahydrofuran (9 mL) held at −78° C. (bath temperature) under an atmosphere of argon. The reaction mixture was allowed to stir for 1 hour at −78° C. N,N-dimethylformamide (732.4 mg, 775.8 μL, 10.02 mmol) was then slowly added to the cold reaction mixture. The reaction mixture was then allowed to slowly warm to room temperature. After stirring for 3 hours at room temperature the crude material was diluted with 25 mL of tetrahydrofuran, washed with a 1M solution of sodium hydroxide, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified on 80 g of silica gel utilizing a gradient of 0-70% ethyl acetate in hexanes to yield tert-butyl 6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (280 mg, 25%) as a white solid. ESI-MS m/z calc. 330.2, found 331.1 (M+1)+; Retention time: 0.94 minutes. 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J=4.0 Hz, 1H), 5.97 (d, J=4.0 Hz, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.98-3.76 (m, 2H), 3.36 (t, J=6.0 Hz, 2H), 3.30-3.08 (m, 2H), 2.36 (s, 3H), 2.09-1.98 (m, 2H), 1.84-1.66 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:14])[CH:6]=1)[CH3:3].[CH3:15]O>>[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:15])=[O:10])=[C:7]([OH:14])[CH:6]=1)[CH3:3]
Reactant: CO
Reactant: CCOc1ccc(C(=O)O)c(O)c1
Agent: Cl
Product: CCOc1ccc(C(=O)OC)c(O)c1
Temperature: 15 °C

Procedure:
Hydrogen chloride was bubbled into a stirred solution of 4-ethoxy-2-hydroxybenzoic acid (10.10 g, 0.554 mol) in methanol (2000 mL) until the solution was saturated. The solution was heated under reflux for 3 days and then cooled to 15° C. This caused the product to crystallize out. The crystals were collected, rinsed with methanol and hexanes, and dried. Methyl 4-ethoxy-2-hydroxybenzoate was obtained as a pale amber solid (49.3 g) melting at 77°-78° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:14]=[N+:15]=[N-:16])[N:10]=[CH:9]1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[C:29]#[CH:30]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:14]2[CH:30]=[C:29]([C:28]([O:32][CH2:33][CH3:34])=[O:31])[N:16]=[N:15]2)[N:10]=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CN=[N+]=[N-])c3)c(F)c2)C(=O)O1
Reactant: C#CC(=O)OCC
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2cn(-c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)cn2)nn1
Yield: 72.9 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-azidomethylimidazol-1-yl)phenyl )-2-oxooxazolidin-5-yl-methyl]acetamide (200 mg, 0.54 mM) and ethyl propiolate (79 mg, 0.81 mM) were dissolved in acetonitrile (10 ml) and heated under reflux for 3 hours. Further ethyl propio late (79 mg) was added, and heting continued for a total of 7 hours. Solvent was evaporated, the residue dissolved in the minimum volume of dichloromethane, and chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (184 mg), containing about 10% of the 5-ethoxycarbonyl isomer.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F.C(N(C(C)C)CC)(C)C>CS(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of t-butyl 1-piperazinecarboxylate 38 (1.0 g., 5.37 mmole), 3-chloro-4-fluoronitrobenzene (0.94 g., 5.37 mmole) and diisopropylethylamine (0.70 g., 5.4 mmole) in DMSO (30 mL.) was heated 16 hours at 100°, cooled to r.t. and poured into ice water (300 mL.). The suspension was extracted with ethyl acetate (2×60 mL.). The combined organic layers were washed with water (3×40 mL.), dried over Na2SO4 and evaporated to dryness to give an orange solid which was recrystallized twice from methanol to give the title compound, 1.2 g. MS (M+H)+ 342.0
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>CS(C)=O.O>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCCCl)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
Diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (3 g, 9.37 mmol) was dissolved in dimethyl sulfoxide (20 ml), and sodium hydride (60%, 525 mg, 13.11 mmol) was added to the resulting solution followed by stirring for 1 hour at room temperature. 5-Bromo-1-chloropentane (7.4 ml, 56.2 mmol) was added to the reaction mixture, followed by stirring for 1.5 hours at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane=1/4) to give diethyl 2-(5-chloropentyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.3 g, Yield 83%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:24][C:23]1[C:22]([CH3:25])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=3)[N:1]=2)=[CH:17][C:16]=1[CH3:15]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2cc1OC
Temperature: 150 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of 2-amino-4,5-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethylacetamide (5 mL) were added 3,5-dimethyl-4-hydroxybenzaldehyde (0.120 g, 0.8 mmol), sodium hydrogen sulphite (58.5%, 0.156 g, 0.88 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h. The reaction mixture was cooled to room temperature and water (40 mL) was added. A white precipitate was formed and filtered off, washed with water and a small amount of methanol and dried under vacuum to give 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (0.230 g, 88% yield) as an off-white solid. Selected data: MS (ES) m/z: 327.12; MP>300° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[CH2:27][CH2:28][C:29]([OH:31])=O)[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:74]([O:78][C:79](=[O:83])[CH2:80][CH2:81][NH2:82])([CH3:77])([CH3:76])[CH3:75]>CN(C=O)C>[C:74]([O:78][C:79](=[O:83])[CH2:80][CH2:81][NH:82][C:29](=[O:31])[CH2:28][CH2:27][C:4]1[C:5]([CH3:26])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:24])[CH3:25])[CH3:22])[CH:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])([CH3:77])([CH3:76])[CH3:75]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)NCCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (43 mg, 0.101 mmol) and DIPEA (40 mg, 0.304 mmol) in DMF (3 mL) is added PyBOP (58 mg, 0.111 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before β-alanine tert.-butyl ester (20 mg, 0.111 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched with 2 mL water, and the mixture is diluted in sat. aq. NaHCO3-solution, and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and dried to give crude 3-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-propionic acid tert-butyl ester (46 mg). This material is dissolved in 4 N HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 18% of 7 N NH3 in methanol to give 3-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-propionic acid (37 mg) as a yellow solid; LC-MS: tR=0.86 min; [M+1]+=494.24.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[C:19]([Cl:26])=[C:20]([OH:25])[C:21]([CH3:24])=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:17][C:18]1[C:19]([Cl:26])=[C:20]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 140 °C
Reaction time: 12 h
Yield: 64.1 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.0 g, 6.1 mmol) in N,N-dimethylformamide (20 mL) were added 3-amino-2-chloro-6-methylphenol (1.9 g, 12 mmol) and potassium carbonate (2.1 g, 15 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→80/20) and precipitated from methanol/diisopropyl ether to give the title compound (1.4 g, 64%) as a pale-yellow powder.
Reaction SMILES: Cl.[CH:2]([N:15]1[CH2:18][CH2:17][CH:16]1[CH2:19][OH:20])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>CS(C)=O>[CH:2]([N:15]1[CH2:18][CH2:17][CH:16]1[CH:19]=[O:20])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCC1CCN1C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 9.0 g of 1-benzhydrylazetidine-2-methanol hydrochloride, 26.1 ml of triethylamine and 60 ml of dimethylsulfoxide were added dropwise a solution of 14.9 g pyridine-sulfur trioxide complex in 60 ml of dimethylsulfoxide. The mixture was stirred at room temperature for 30 minutes, after which it was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, followed by removal of the solvent by distillation. The residue was recrystallized from n-hexane to yield 1-benzhydrylazetidine-2-carbaldehyde as colorless crystals melting at 88°-89° C.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]([O:16]C)=[CH:8][CH:7]=1.O.[OH-].[Na+]>ClCCl>[Cl:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]([OH:16])=[CH:8][CH:7]=1
Reactant: COc1ccc(Cl)c(C(=O)O)c1F
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1c(Cl)ccc(O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
Boron tribromide (1.5 ml, 15.3 mmol) was added dropwise to a solution of 6-chloro-2-fluoro-3-(methyloxy)benzoic acid (intermediate 33, 1.04 g, 5.1 mmol) in dichloromethane (100 ml) at 0° C. under an atmosphere of Argon. The reaction was stirred at room temperature for 18 hrs. Water (5 ml) was added and the solid formed stirred for 5 mins. Sodium hydroxide (2M, 4 ml) was added and the remaining solid dissolved. The layers were separated and the aqueous layer evaporated to afford a colourless solid. This was extracted with ethyl acetate (3×) and the combined organics evaporated to afford the title compound as a yellow solid (831 mg). 1H-NMR δ 7.02 (1H, t, J 10), 7.16 (1H, dd, J 10, 3), 10.48 (1H, s), 13.96 (1H, br s).
Reaction SMILES: Cl.[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=O)=[CH:18]3)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1([F:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:49][C:50]1([F:56])[CH2:55][CH2:54][N:53]([C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:14])=[CH:23][CH:22]=3)=[O:26])[CH2:52][CH2:51]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (74%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:29]([O:28][C:26]([N:20]1[CH2:21][CH2:22][N:23]([S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:24][CH2:25]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(-c3cc(CC)c(=O)[nH]c3C)s2)CC1
Yield: 60.2 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with ethyl piperazine-1-carboxylate as described in Step 5, Example 24 to give the title compound as a solid (60.2% yield). LC/MS: RT 2.93 min; m/e 440 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.4 (1H, s); 7.3 (1H, d), 4.0 (2H, t), 3.5 (4H, m), 3.0 (4H, m), 2.4 (2H, q), 2.36 (3H, s), 1.08 (6H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-benzyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (3.06 g, 10.0 mmol) in dry DMF (30 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/480 mg, 12.0 mmol) in dry DMF (20 ml) under nitrogen at room temperature. The reaction mixture was stirred for one hour at room temperature to which was added dropwise tert-butyl bromoacetate (1.48 ml, 10.0 mmol). The reaction was stirred for a further two hours, diluted with ethyl acetate (100 ml), washed with brine (2×100 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate-hexane (2:5) as eluant. (3.28 g, 78%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:7]=2[CH:20]=1.FC(F)(F)C(O)=O>ClCCl>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])[C:7]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)CNc1noc2ccc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNc1noc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
Preparation I7, Step 5: A solution of tert-butyl 2-(5-(trifluoromethyl)benzo[d]isoxazol-3-ylamino)acetate (367 mg) in dichloromethane (20 mL) at 0° C. was treated with trifluoroacetic acid (2 mL) and stirred at rt for 5 h. The mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel, eluting with 10% to 50% (v/v) ethyl acetate-hexane, to provide 2-(5-(trifluoromethyl)benzo[d]isoxazol-3-ylamino)acetic acid (270 mg) as an off-white solid. MS found: (M+H)+=261.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[NH2:36][CH:37]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=1)[C:38]([N:40]([CH2:44][CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH:41]([CH3:43])[CH3:42])=[O:39]>CN(C=O)C.C(Cl)CCl>[Cl:59][C:56]1[CH:55]=[CH:54][C:53]([CH2:52][CH:37]([NH:36][C:33](=[O:35])[CH2:32][CH2:31][NH:30][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[C:38]([N:40]([CH2:44][CH:45]([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])[CH:41]([CH3:42])[CH3:43])=[O:39])=[CH:58][CH:57]=1
Reactant: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC
Reactant: COc1ccc(S(=O)(=O)NCCC(=O)O)cc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)CCNS(=O)(=O)c1ccc(OC)cc1)C(C)C)OCC
Reaction time: 12 h

Procedure:
52 mg of EDC, 45 mg of HOBt and 100 μl of N-ethylmorpholine are added to a solution of 124 mg of 3-(4-methoxybenzenesulfonylamino)propionic acid in 1 ml of DMF. A solution of 100 mg of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide in 1 ml of DMF is added dropwise thereto, and the mixture is left to stir for 12 h. The reaction solution is filtered, mixed with ethyl acetate and then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying of the organic phase with Chromabond XTR is followed by concentration under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=598.16 (calculated); measured value (M−C2H6O+H)+: 552.1
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40]C3CCCCO3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][CH2:39][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:48])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[O:38][N:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)no2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cc(CO)no3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-morpholin-4-yl-2-(3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M23) (57 mg, 0.08 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (11 mg).
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]O)[CH:14]=1.S(Cl)([Cl:23])=O>>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][Cl:23])[CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1c(NCCCOc2cccc(CO)c2)c(=O)c1=O
Product: Nc1c(NCCCOc2cccc(CCl)c2)c(=O)c1=O

Procedure:
When 1-amino-2-[3-(3-hydroxymethyl-phenoxy)propylamino]-1-cyclobutene-3,4-dione is treated with at least one equivalent of thionyl chloride, there is thereby produced the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27](O)=[O:28])[C:10]=2[C:30](O)=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:36][C:35]=1[Cl:46].O>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:46][C:35]1[CH:36]=[C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:38]=[CH:39][C:34]=1[N:33]1[C:27](=[O:28])[C:11]2[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]3=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]=2[C:30]1=[O:31]
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C(O)c1c(C(=O)O)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)c(Cl)c1

Procedure:
A mixture of 1 1,4-bis[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (5.0 g, 11.68 mmol), ethyl (4-amino-3-chlorophenyl)acetate (4.74 g, 22.2 mmol) and DMAP (0.427 g, 3.59 mmol) were heated to 120° C. in acetic acid (20 ml) for 18 hours. Water was added and the mixture and resulting brown solid collected by filtration and washed with water. This was triturated with ether to give a cream solid which was collected by filtration and dried in the vacuum oven (5.34 g, 8.83 mmol). LC/MS: Rt=4.15, [MH]+ 606.