Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].[Cl-].[NH4+].CC[N:16](CC)CC>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:16])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(N)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-4-methylbenzoic acid (1.5 g, 7.0 mmol) in thionyl chloride (10 mL) was heated to 80° C. for 1 h. The solvent was removed in vacuo and the residue was dissolved in DCM (16 mL) at 0° C. under argon before adding ammonium chloride (410 mg, 7.7 mmol) and Et3N (2.43 mL, 17.4 mmol). The reaction was stirred at 0° C. for 15 min then allowed to warm to rt over 16 h. The solvent was removed in vacuo and the mixture partitioned between EtOAc (120 mL) and 1M NaOH (60 mL). The organic phase was washed with 1M NaOH (60 mL), brine (60 mL) and dried (MgSO4). The solvent was removed in vacuo. Trituration with ether and then MeOH gave the title compound: RT=2.78 min; m/z (ES+)=214.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:10]Br.N#N>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:8]([CH3:9])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: BrBr
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of methyl 3-oxopentanoate (9.62 mL, 76.8 mmoles, Acros) in carbon tetrachloride (60 mL) is added dropwise over a period of 45 minutes a solution of bromine (3.96 mL, 76.8 mmoles) in carbon tetrachloride (10 mL). After 30 minutes, let stir at room temperature for one hour. Bubbled N2 through reaction mixture for twenty minutes. Concentrated to yield the title compound as a brown oil. MS (EI) 208, 210 (M)+, Br pattern.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH2:48])=[S:47])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCl>[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH:48][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[S:47])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC(=S)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(=S)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1-tert-Butoxycarbonylpiperidine-4-carboxylic acid (0.70 g, 3.05 mmol, Aldrich) and HATU (1.74 g, 4.58 mmol) were suspended in dichloromethane (10.0 ml) at room temperature for 20 minutes, followed by addition of 4-fluorothiobenzamide (0.47 g, 3.05 mmol) in one portion. The mixture was stirred at room temperature for 40 minutes, and DIEA (1.18 g, 9.16 mmol) was added. After stirring at room temperature overnight, the solvent was removed under reduced pressure. The residue was passed through a silica gel cartridge using a gradient of 0˜50% ethyl acetate in hexanes to give the title compound as a bright yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C@@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([N:30](C)[C:31](=O)OC(C)(C)C)[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C@@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([NH:30][CH3:31])[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: COc1ccccc1NC(=O)[C@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
For Example 9: To a solution of tert-butyl (R)-(2S)-1-((2S)-1-(2-(2-methoxyphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (36 mg, 65.0 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (1 mL, 13.0 mmol, Eq: 200) and the resulting solution was stirred at rt. After 2 h, the reaction mixture was concentrated in vacuo, the residue was treated with saturated aqueous NaHCO3 (5 mL) and the resulting mixture was extracted with DCM (2×5 mL). The combined organic layers were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give (R)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-methoxyphenyl)-amide (22 mg), m/z=454 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11](O)[C:10]2[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:40]=[N+:41]=[N-:42])[C:10]2[CH:16]=[C:17]([CH2:24][CH3:25])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Yield: 71.3 %

Procedure:
Heat a mixture of (R)-7-ethyl-5-hydroxy-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (7.59 g, 21.12 mmol), diphenylphosphoryl azide (DPPA, 5.50 mL, 25.64 mmol) and DBU (3.95 mL, 26.41 mmol) in toluene (200 mL) at 65° C. under nitrogen for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless oil (5.79 g, 71%): 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 18H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 1H), 7.31-7.45 (m, 2H); APCI MS m/z 356 (M−N2)−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[Cl-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.Cl>C(O)C>[CH2:29]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
27.4 g (0.2 mol) of 4-aminobenzoic acid, 11.2 g of KOH, 64 g (0.21 mol) of 1-bromohexadecane and 4.64 g (10 mmol) of hexadecyltributylphosphonium chloride were suspended in 250 ml of ethanol (96%) and the reaction mixture was stirred for 12 hours at reflux temperature. While the solution was still hot, there were added, drop by drop, 80 ml of conc. HCl and the reaction mixture was left to cool down to ambient temperature. Thereupon the precipitated product was separated on a suction filter, washed with water and dried. After the crystallization of the crude product from benzene, there was obtained the 4-(n-hexadecylamino)-benzoic acid, m.p. 107°-107° C., complete m.p. 122°-126° C., which could be optionally converted into its sodium salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CN(C)CCO
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and PPh3 (4 g) in THF (50 ml) was added DEAD (2.6 ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer was basified with NaHCO3, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2SO4 and evaporated to give (2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl)dimethylamine, was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:19]#[N:20])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: N#Cc1cccc(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cccc(C#N)c3)cccc2c1N
Yield: 85.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3-cyanophenylboronic acid (147 mg, 1.000 mmol) were reacted to afford the title compound (138 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 8.06-7.89 (m, 3H), 7.85-7.69 (m, 3H), 7.65-7.57 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=332 M+H) HPLC 1.93 min.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cccc(Cl)c1Cl
Product: Clc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1Cl

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2,3-dichlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 370.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (s, 1H); 8.44 (d, J=5.5 Hz, 1H); 7.93 (br s, 1H); 7.85 (d, J=8.3 Hz, 1H); 7.19 (t, J=5.8 Hz, 1H); 6.86 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.86 (d, J=6.4 Hz, 2H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:28])[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:16]1)([CH3:10])([CH3:9])[CH3:8].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:7]([O:11][C:12](=[O:28])[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:26]=2)[CH2:16]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Oc3ccccc3)cc2)C1
Temperature: 140 °C
Yield: 116.2 %

Procedure:
To a mixture of Cs2CO3 (70 mg; 0.21 mmol), 3-[2-(4-Hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (33.8 mg, 0.11 mmol) and bromobenzene (12.6 μL, 0.12 mmol) was added 0.5 mL of a freshly prepared catalyst stock solution (see below) in a 2-5 mL Biotage® microwave vial. The vial was briefly flushed with N2 and sealed to maintain a semi-inert atmosphere. The resulting mixture was heated for 22 h, at 140° C. After cooling to room temperature, water (5 mL) was added and the mixture was extracted with EtOAc (1×7.5 mL, 2×5 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by preparative TLC (SiO2, CH2Cl2/MeOH 99:1) to afford 3-[2-(4-phenoxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (49 mg). The catalyst stock solution was prepared as follows: To a suspension of copper(I)iodide (73 mg, 0.16 mmol) in anhydrous toluene (9 mL) was added 1-butylimidazole (127 μL; 120 mg; 0.41 mmol). The solution was purged with N2 for 15 min. and vigorously agitated until all the CuI had fully dissolved.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:19]([O-])=O)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[Pd]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a solution of 1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.8 g, 9.24 mmol) in tetrahydrofuran (50 mL) was added 10% palladium on activated carbon (0.98 g). The resulting mixture was stirred under hydrogen (50 psi) for 48 h at room temperature. The catalyst was removed by filtration and the filtrate was concentrated to afford 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (2.52 g, 100%) as a yellow oil which was used in the next step without purification: LC/MS m/e calcd for C13H11N3O2S [M+H]+ 274.32, observed 274.1.
Reaction SMILES: [Cl-].[NH4+].[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])=[CH:5][CH:4]=1.C(O)C>O.[Fe]>[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][C:10]=2[Cl:19])=[CH:5][CH:4]=1
Reactant: Nc1nc(-c2ccc(-c3ccccc3)cc2)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(-c3ccccc3)cc2)nc1N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Ammonium chloride (632 mg, 11.82 mmol) and iron (1320 mg, 23.64 mmol) were added to a stirred mixture of 6-([1,1′-biphenyl]-4-yl)-5-chloro-3-nitropyridin-2-amine (550 mg, 1.688 mmol) in water (2 ml)/Ethanol (2 mL) and the mixture was stirred at 60° C. for 3 h. The mixture was filtered through Celite™, rinsing with ethyl acetate (100 mL). Water (80 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (saturated, 80 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel Biotage™ 40S, eluting with 0-60% EtOAc/hexane to give title compound. LC-MS: calculated for C17H14ClN3 295.09 observed m/e: 296.12 (M+H)+ (Rt 1.09/2 min).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:36]([CH2:38][CH2:39][CH3:40])[CH3:37]>CN(C=O)C>[CH3:37][CH:36]([NH:26][S:25]([N:20]1[C:21]2([CH2:22][CH2:23]2)[CH2:24][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:18][CH2:19]1)(=[O:27])=[O:28])[CH2:38][CH2:39][CH3:40]
Reactant: CCCC(C)Br
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(C)NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2CO3 (0.147 mmol) and 2-bromopentane (0.074 mmol). Stirred at 60° C. for 16 h and then filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100° C. for 1 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [C:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:44]=[C:43]([CH2:45][CH2:46][CH3:47])[C:27]([O:28][CH:29]([C:34]2[CH:39]=[CH:38][C:37]3[O:40][CH2:41][O:42][C:36]=3[CH:35]=2)[C:30]([O:32][CH3:33])=[O:31])=[C:26]([Cl:48])[CH:25]=1>CN(C=O)C>[C:30]([CH:29]([C:34]1[CH:39]=[CH:38][C:37]2[O:40][CH2:41][O:42][C:36]=2[CH:35]=1)[O:28][C:27]1[C:43]([CH2:45][CH2:46][CH3:47])=[CH:44][C:24]([CH2:23][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]2=[O:15])=[CH:25][C:26]=1[Cl:48])([O:32][CH3:33])=[O:31]
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reactant: CCCc1cc(CBr)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 0.069 g (0.33 mmol) of 1-carboethoxy-2-benzimidazolinone dissolved in 0.6 mL DMF was added 0.217 g (0.66 mmol) of powdered cesium carbonate and the resulting suspension was stirred under a nitrogen atmosphere at room temperature for 30 minutes. A solution of the product of step E in 0.5 mL DMF was then added and the reaction mixture was stirred for an additional 15 hours. The mixture was then partitioned between EtOAc and water and extracted. The organic layer was separated, dried (MgSO4), filtered and evaporated, and the residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.088 g (45%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: Nc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)Nc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and aniline.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:29]([C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:23]3[N:22]=[C:21]([C:20]([F:35])([F:19])[F:36])[O:25][N:24]=3)[CH:27]=2)=[O:30])[CH2:4][CH:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCNCC1c1nc(-c2ccccc2)cs1
Product: CN1CCN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CC1c1nc(-c2ccccc2)cs1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(1-methylpiperazin-2-yl)-4-phenylthiazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (30 mg, yield 32%) as colorless viscous liquid. 1H NMR (400 MHz, CDCl3) δ 8.17-8.16 (m, 2H), 7.93-7.79 (m, 2H), 7.64-7.62 (m, 2H), 7.48-7.32 (m, 4H), 4.78-4.53 (m, 1H), 3.85-3.69 (m, 2H), 3.49-3.30 (m, 2H), 3.17-2.98 (m, 1H), 2.53-2.40 (m, 1H), 2.32 (s, 3H). MS (ESI) m/z: Calculated for C24H20F3N5O2S: 499.12. found: 500.2 (M+H)+
Reaction SMILES: [NH3:1].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:12](Cl)(=[O:14])=[O:13]>O1CCCC1>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:12]([NH2:1])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1sccc1C1OCCO1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sccc1C1OCCO1

Procedure:
To 5 ml of liquified ammonia gas dissolved in 50 ml of tetrahydrofuran was added dropwise with stirring and cooling 12.7 g of 3-(1,3-dioxolan-2-yl)thiophene-2-sulfonyl chloride. After stirring overnight at ambient temperature, the tetrahydrofuran was removed in vacuo, water was added to the residue and the mixture was extracted twice with 75 ml of methylene chloride. After washing the combined methylene chloride extracts with water, drying over magnesium sulfate, filtering off the drying agent and evaporation of the methylene chloride, an oily solid residue was obtained. This was chromatographed through silica gel using 1:1 ethyl acetate-hexanes as eluant (Rf 0.35). Evaporation of the solvent mixture yielded 2.2 g of the desired product, as a waxy solid. Infrared absorption spectra showed peaks at 3360, 3260, 1340 and 1140 cm-1, consistent for a primary sulfonamide. Mass spectrum analysis: calc. 235, found 234 (Mass-1H).
Reaction SMILES: C([C@H]1COC(=O)N1[C:10](=[O:18])[C@:11]([CH2:15][O:16][CH3:17])([CH3:14])[CH:12]=[CH2:13])(C)C.OO.O.[OH-].[Li+].S(S([O-])=O)([O-])(=O)=[O:25].[Na+].[Na+].Cl>O1CCCC1.O>[CH3:17][O:16][CH2:15][C@:11]([CH3:14])([CH:12]=[CH2:13])[C:10]([OH:18])=[O:25]
Reactant: C=C[C@](C)(COC)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@@](C)(COC)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a stirred solution of (S)-4-isopropyl-3-((R)-2-methoxymethyl-2-methyl-but-3-enoyl)-oxazolidin-2-one (1.5 g, 5.87 mmol) in tetrahydrofuran (30 mL) and water (15 mL) at 0° C., was added hydrogen peroxide (30% solution, 3 mL, 29.35 mmol) and lithium hydroxide monohydrate (0.59 g, 11.75 mmol). The reaction mixture was stirred at 0° C. for 3 h then was treated with saturated sodium metabisulfite and the pH of the solution was adjusted to 1 with dropwise addition of hydrochloric acid (10 M). The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The crude residue was purified by silica gel chromatography using a Biotage KP-Sil 50 g cartridge, eluting with a gradient of iso-hexanes/ethyl acetate 1:0 to 3:1 to give the title product (0.546 g, 65%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.36 (s, 3H), 3.42 (s, 3H), 3.45 (d, J=8.9 Hz, 1H), 3.62 (d, J=8.9 Hz, 1H), 5.20-5.30 (m, 2H), 6.01 (dd, J=17.6, 10.7 Hz, 1H), 9.80-11.80 (br. s, 1H).