Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:17])[CH3:16].Br[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41]>C(=O)=O.CC(C)=O.O1CCCC1>[C:15]([O:19][C:20](=[O:36])[NH:21][C@H:22]([C@@H:30]1[CH2:34][C@@H:33]([CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])[C:32](=[O:35])[O:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: CC(C)=CCBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a flame dried round bottom flask under a nitrogen atmosphere was added tetrahydrofuran (40 mL) followed by 1,1,1,3,3,3-hexamethyldisilazane (8 mL, 37.8 mmol). The mixture was cooled to 0° C. and n-butyl lithium (14.5 mL of a 2.5 M solution in hexanes, 36.0 mmol) was added. The mixture was stirred for 15 minutes, then cooled to −78° C. in dry ice/acetone bath. {1(S)-[5-Oxo-tetrahydro-furan-2(S)-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (5 g, 16.4 mmol) (prepared by the method of Fray, J. Org. Chem., (51) 4828 (1986)) dissolved in tetrahydrofuran (50 mL) was added dropwise via syringe and stirring continued for 30 minutes. A solution of 4-bromo-2-methyl-2-butene (2.07 mL, 18.0 mmol) in 40 mL of THF was added dropwise via syringe. Stirring was continued for 3 hours during which time the temperature rose to −60° C. The mixture was quenched by slow addition of saturated, aqueous ammonium chloride (25 mL). Upon warming to room temperature, the solution was diluted with ether (300 mL) and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (NaHCO3)(2×100 mL), and 100 mL brine. The organic layer was dried over magnesium sulfate (MgSO4) and the solvent removed under reduced pressure. Thin layer chromatography in 1:2 hexane/diethyl ether (Et2O) revealed product with an Rf of 0.8. The resulting crude oil was chromatographed on silica gel (225 g) eluting with 2:1 hexanes/diethyl ether to provide 4.73 g (77%) of the title compound. TLC: 1:2 Hexanes/Et2O Rf: 0.8. 1H NMR (400 MHz, CDCl3): δ7.27 ppm (5H, m), 5.02 (1H, b), 4.52 (1H, d, J=9.3 Hz), 4.42 (1H, t, J=7.1 Hz), 3.98 (1H, dt, J=8.5, 7.8 Hz), 2.93 (2H, m), 2.88 (1H, b), 2.68 (1H, m), 2.41 (1H, m), 2.24 (1H, m), 1.92 (1H, m), 1.65 (3H,s), 1.58 (3H,s), 1.37 (9H, s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[C:23]1([C:29]#[C:30][CH:31]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:31][C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=CC#Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCC#Cc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 1940 mg of phenylpropargylaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 14 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.27 g of 7-methoxy-1-(2-(4-(3-phenyl-2-propyn-1-ylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a brown oil and 0.23 g of 1-(2-(4-(bis(3-phenyl-2-propyn-1-ylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17]N(C=O)C.[H-].[Na+].CI>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:17])[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (100 mL). To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, methyl iodide (2.74 mL, 0.042 mol) was added dropwise. After the dropwise addition, the reaction was conducted for 2 h. After completion of the reaction, the reaction solution was poured into water (600 mL). A great deal of red solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce an orange red solid (7.6 g) in a yield of 80.0%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][OH:20])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:18][CH2:19][O:20][C:28]2[CH:29]=[CH:30][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=2)=[CH:7][C:8]=1[C:14]([F:16])([F:17])[F:15])#[N:11]
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (APCI) m/z 418 (M+1).
Reaction SMILES: I.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](SC)=[NH:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[O:15]=[C:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C:28]([NH:30][NH2:31])=O)[CH:22]=2)[NH:17]1.O>CS(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[Cl:9])[CH2:10][C:11]1[NH:12][C:28]([CH2:27][O:26][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:15])[CH2:25][CH2:24]3)=[N:30][N:31]=1
Reactant: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Reactant: CSC(=N)Cc1ccc(Cl)c(Cl)c1
Agent: I
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2cc(OCc3nnc(Cc4ccc(Cl)c(Cl)c4)[nH]3)ccc2N1
Temperature: 115 °C

Procedure:
To the stirred solution of methyl 2-(3,4-dichlorophenyl)ethanimidothioate hydroiodide (0.184 g, 0.51 mmol) in dry DMSO (1 mL) were added 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (0.120 g, 0.51 mmol) and TEA (0.103 g, 1.02 mmol) and heated at 115° C. in a seal tube overnight. Water was added to the reaction mixture. The solid precipate was filtered, dried and purified by preparative HPLC on a Kromasil C4 column (250×20 mm) using a gradient of ACN in 0.1% TFA (0-100%) to give 6-((5-(3,4-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as an off white solid (0.070 g; 34%). 1HNMR 400 MHz, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.82 (t, J=8.00 Hz, 2H), 4.09 (s, 2H), 5.01 (s, 2H), 6.75-6.76 (m, 2H), 6.88 (s, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.59 (d, J=8.00 Hz, 2H), 9.91 (s, 1H), 13.87 (bs, 1H). LCMS: RT 1.71 min; LCMS (ES-API), m/z 403.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[OH:12].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24](Cl)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([O:12][C:3]3[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([F:10])[C:4]=3[F:11])(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,4,5,6-Pentafluorophenol (2.73 g, 14.82 mmol) was dissolved in DCM (49.4 ml). 1-chloroisoquinoline-6-sulfonyl chloride (2.59 g, 9.88 mmol) was added, followed by the dropwise addition of triethylamine (2.066 ml, 14.82 mmol). The reaction was stirred overnight at room temperature. The reaction was concentrated and purified by silica gel chromatography (40 g column, gradient elution 0 to 50% Et2O:Heptane) to afford perfluorophenyl 1-chloroisoquinoline-6-sulfonate as a white solid. m/z (ESI) 410.0 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[N:22]=[C:23]([NH:26]C(=O)C)[S:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[C:8]1([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1nc(CN2CCN(c3ccccc3)CC2)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(CN2CCN(c3ccccc3)CC2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of N-(4-((4-phenylpiperazin-1-yl)methyl) thiazol-2-yl)acetamide TFA salt (30 mg, 0.07 mmol) in THF (2 ml) was added 6N hydrochloric acid (2 ml). The reaction was heated at reflux for 2.5 hours, and then stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to give the hydrochloride salt of 4-((4-phenylpiperazin-1-yl)methyl)thiazol-2-amine 94a as a tan solid, 20 mg (92% yield). LC/MS m/z 275.24 (M+H)+); HPLC Rt: 0.77 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33](O)=[O:34])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:34])[CH2:27][CH2:26]1
Reactant: CN1CCN(c2ccccc2C(=O)O)CC1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccccc2N2CCN(C)CC2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-(4-Methyl-piperazin-1-yl)-benzoic acid. LC-MS (basic): tR=0.86 min; [M+H]+=530.1.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]#[C:19][CH3:20])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C(N(CC)CC)C.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C@@:3]([OH:5])([CH3:4])[C:2]([F:1])([F:21])[F:22])=[CH:11][CH:10]=3)[CH:13]([C:18]#[C:19][CH3:20])[CH2:14]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC#CC1CNCCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of (2S)-1,1,1-trifluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (0.190 g, 0.608 mmol) in DCM (5.0 mL) was added triethylamine (0.254 mL, 1.83 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was cooled to 0° C. and 6-chloropyridine-3-sulfonyl chloride (0.155 g, 0.730 mmol, Organic Process Research & Development 2009, 13, 875) was added in one portion. After the addition, the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was concentrated and the crude product was purified by column chromatography (40 g of silica, 10 to 30% acetone in hexanes) to afford (2S)-2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.240 g) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([F:18])[CH2:20]2)[CH:3]=1
Reactant: FC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC(F)C1
Temperature: 40 °C
Yield: 97.8 %

Procedure:
A solution of 4-chloro-2-fluoro-1-nitro-benzene (0.30 g, 1.7 mmol) in toluene (5 mL) was treated with solid Na2CO3 (0.40 g, 3.7 mmol) and 3-fluoropiperidine (0.25 mg, 1.8 mmol) and heated to 40° C. for 6 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.43 g, 98%) as a bright yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 7.76 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.95 (dd, 1H, J=8.8, 2.4 Hz), 4.86-4.67 (m, 1H), 3.46-3.35 (m, 1H), 3.15-3.06 (m, 2H), 2.99-2.92 (m, 1H), 2.10-1.90 (m, 2H), 1.88-1.69 (m, 2H). LC-MS (ESI, m/z): Calcd. for C11H12ClFN2O2 259.1 (M+H), found 259.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[C:9]=2[CH:25]=1)[CH2:2][CH3:3].[CH:29]([NH:31][NH2:32])=O>C(O)C>[CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:29]=[N:31][N:32]=[C:13]3[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[C:9]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)c1ccc2c(c1)C(c1ccccc1[N+](=O)[O-])=NCC(=S)N2
Reactant: NNC=O
Solvent: CCO
Product: CCCN(CCC)c1ccc2c(c1)C(c1ccccc1[N+](=O)[O-])=NCc1nncn1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-(dipropylamino)-1,3-dihydro-5-(o-nitrophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with formic acid hydrazide and the resulting product heated to 250° C. to give 8-(dipropylamino)-6-(o-nitrophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:9]([OH:15])[CH2:10][O:11][CH2:12][CH2:13]O>[Pd]>[OH:15][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:5][CH:4]([CH3:6])[CH2:3][CH2:2][C:1]([O:8][CH2:13][CH2:12][O:11][CH2:10][CH2:9][OH:15])=[O:7]
Reactant: OCCOCCO
Reactant: CC(=O)CCC(=O)O
Agent: [Pd]
Product: CC(CCC(=O)OCCOCCO)OCCOCCO
Temperature: 230 °C
Yield: 23.4 %

Procedure:
Levulinic acid (11.6 g; 0.1 mol), diethylene glycol (63.6 g; 0.6 mol), and 2.32 g of 10% Pd/C from Aldrich (20 wt % relative to levulinic acid) are charged to a Parr reactor, purged with nitrogen three times, heated to 230° C. with stirring, and reacted with 1000 psi of hydrogen for 65 hrs. GC analysis reveals that the reaction is complete. Diethylene glycol is distilled off at 70-72° C./0.06 mm to give 15.6 g of the crude product, which is chromatographed on silica gel using at first neat methylene chloride and then methylene chloride-methanol from 30:1 to isolate 6.9 g of 2-(2-hydroxyethoxy)ethyl 4-(2-(2-hydroxyethoxy)ethoxy)pentanoate. 1H NMR (δ, ppm, CDCl3): 1.16 d (3H, CH3), 1.81 m (2H, CH2), 2.46 m (2H, CH2CO), 3.1 (broad, 2H, OH), 3.50 m (3H, CH2O, CH), 3.61 m (14H, 7CH2O), 4.25 m (2H, COOCH2). 13C NMR (δ, ppm, CDCl3): 19.30 (CH3); 30.01; 31.27 (CH2 groups); 61.38; 61.54; 63.22; 67.64; 68.88; 70.48; 72.33; 72.37 (CH2O groups), 74.68 (CH), 173.57 (COO). Mass spectrum: m/e 294 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.CCN(C(C)C)C(C)C.[NH:20]1[CH:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:22][CH2:21]1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:20]2[CH:28]3[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:22][CH2:21]2)=[O:9])[CH:3]=1
Reactant: C1CCC2NCCC2C1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.517 g (2.92 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 10 mL dichloromethane were combined with 1.07 mL (6.00 mmol) DIPEA. 0.73 g (2.92 mmol) octahydroindole in 10 mL DCM was slowly added dropwise. After 2 h stirring at RT the mixture was diluted with dichloromethane and extracted with water. The organic phase was separated off, dried on sodium sulphate, filtered, evaporated down i. vac. and dried.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(Cl)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-5-(trifluoromethyl)benzoic acid (CAS RN 39226-97-6) after a reaction time of 68 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). The product-containing fractions were pooled and evaporated. The product was dissolved in EtOAc and extracted three time with 1M aqueous HCl. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified a second time by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Light brown solid (47%). MS (ESI): m/z=405.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:18][C:19]([O:21]CC)=O)([CH3:17])[CH2:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:4]12[CH2:5][N:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]3[C:3]1=[C:2]([CH:10]=[CH:9][CH:8]=3)[NH:1][C:19](=[O:21])[CH2:18]2
Reactant: CCOC(=O)CN1CC(C)(CC(=O)OCC)c2c(N)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CC2(C)CC(=O)Nc3cccc1c32
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of diethyl 2,2′-(4-amino-3-methyl-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step D (410 mg, 1.28 mmol) in toluene (100 mL) was added p-toluenesulfonic acid monohydrate (10 mg, 0.052 mmol) and the mixture was heated at reflux. After 20 min, the reaction was allowed to cool to ambient temperature and the mixture was partitioned between EtOAc (300 mL) and aqueous NaHCO3 (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give the racemic product. The enantiomers were resolved by HPLC, utilizing a Chiralpak AS column and eluting with hexane:EtOH 40:60. The first major peak to elute was ethyl (2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer A, the title compound, and the second major peak to elute was ethyl (2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer B. MS: m/z=275 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]1=[O:17].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:18]([O:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10](=[O:17])[CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(O)cc(=O)n1-c1c(Cl)cccc1Cl
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.125 g, 0.46 mmol) and benzylbromide (0.1 mL) in DMF (2.5 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water, dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes to afford the title compound (0.11 g) as a pale yellow syrup: 1H-NMR (CD3OD) δ: 7.61 (m, 2H), 7.55-7.3 (m, 6H), 6.23 (d, 1H, J=2.0 Hz), 6.01 (d, 1H, J=2.0 Hz), 5.12 (s, 2H), and 1.93 (s, 3H); ES-MS m/z=360 (MH+); HR-MS, m/z calc C19H16NO2Cl2, 360.0553, found 360.0569.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][CH2:26][CH2:27][CH3:28])=[O:10])[CH:7]=1
Reactant: CCCN
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 51.3 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and n-propylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (207 mg, yield 51%). MS calcd for (C18H22BN3O5S): 403.1. MS found (ESI negative): (M−H)−=402.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 9.17 (bs, 1H), 7.99 (t, J=5.6 Hz, 1H), 7.42 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.46 (d, J=2 Hz, 1H)), 6.35 (d, J=8.8, 2.4 Hz, 1H), 4.87 (s, 2H), 3.78 (s, 2H), 3.05 (m, 2H), 1.43 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:13]([NH:15][C:16]1S[CH:18]=[CH:19][N:20]=1)=[O:14].N[C:26]1[CH:31]=CC=CN=1>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:13]([NH:15][C:16]1[CH:31]=[CH:26][CH:18]=[CH:19][N:20]=1)=[O:14]
Reactant: CC(C)CC(C(=O)Nc1nccs1)N1C(=O)c2ccccc2C1=O
Reactant: Nc1ccccn1
Product: CC(C)CC(C(=O)Nc1ccccn1)N1C(=O)c2ccccc2C1=O

Procedure:
The title compound was synthesized according to the method described in connection with Compound 13, except that 2-aminopyridine was used. 1H NMR (400 MHz, MeOH-d4) δ: 8.34 (dd, J=1.2, 6.0 Hz, 1H), 8.12-8.17 (m, 1H), 7.91-7.94 (m, 2H), 7.85-7.88 (m, 2H), 7.79 (d, J=7.2 Hz, 1H), 7.38-7.43 (m, 1H), 5.19 (dd, J=4.4, 11.2 Hz, 1H) 2.35-2.44 (m, 1H), 1.97-2.06 (m, 1H), 1.51 (m, 1H) 1.0 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H). [M+H] calc'd for C19H19N3O3, 338. found, 338.