Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[C:34]=1[Cl:35])[O:5][C@@H:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C@@H:7]([C:11]1[CH:24]=[CH:23][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].[CH3:40][N:41](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[Cl:35][C:34]1[C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:4]([O:5][C@@H:6]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C@@H:7]([C:11]2[CH:24]=[CH:23][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:13][CH:12]=2)[CH2:8][CH2:9][CH3:10])=[CH:3][C:2]=1[C:40]#[N:41]
Reactant: CN(C)C=O
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1cc(Br)c(Cl)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1cc(C#N)c(Cl)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
The product from Step B (200 mg, 0.309 mmol), (Ph3P)4Pd (107 mg, 0.093 mmol), and zinc cyanide (54.4 mg, 0.473 mmol) were stirred in DMF (3 mL) at 120° C. for 24 hours. After cooling to RT, the mixture was filtered through celite, then the filtrate was concentrated. The resulting residue was purified by reverse phase HPLC eluting with 60-100% acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the title compound. 1H NMR (500 MHz, (CD3)2CO): δ 7.78 (d, J=8.5 Hz, 2H); 7.62 (d, J=3.0 Hz, 1H); 7.56 (d, 2.5 Hz, 1H); 7.41 (d, J=3.0 Hz, 2H); 7.39 (d, J=2.5 Hz, 2H); 7.34 (d, J=8.5 Hz, 2H); 5.90 (d, J=7.0 Hz, 1H); 3.61 (m, 2H); 3.29 (m, 1H); 2.63 (m, 2H); 2.62-1.77 (m, 1H); 1.62-1.55 (m, 1H); 1.15-1.08 (m, 2H); 0.76 (t, J=7.2 Hz, 3H); LC3 4.09 min. (M+H)+ 593.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[C:23]([NH2:24])=[C:22]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.N1C=CC=CC=1.C(OCC)C>C1COCC1>[Cl:13][C:14]1[C:23]2[N:24]=[C:1]([OH:2])[N:25]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cccnc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1nc2c(Cl)nc3ccccc3c2n1Cc1cccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
1,1′-Carbonyldiimidazole (3.20 g, 19.7 mmol) was added to 2-chloro-N4-(pyridin-3-ylmethyl)quinoline-3,4-diamine (5.09 g, 17.9 mmol) in THF (100 mL), and the resulting suspension was heated at 80° C. for three days. An analysis by LC/MS indicated the presence of starting material, and pyridine (100 mL) and additional 1,1′-carbonyldiimidazole (1 equivalent) were added. The reaction was stirred for two hours at 80° C., and additional 1,1′-carbonyldiimidazole (1 equivalent) was added. The reaction was stirred overnight at 80° C. and allowed to cool; a solid was present. Diethyl ether (50 mL) was added, and the solid was isolated by filtration and dried under vacuum to provide 4.2 g of 4-chloro-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol as a gray solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=2)[NH:3]1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(CC)CC>>[N:20]1([S:16]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])(=[O:18])=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc2[nH]1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Product: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)N3CCCCC3)ccc2[nH]1
Yield: 43.4 %

Procedure:
Condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 50 mg, 160 μmol) with piperidine (17 μL, 168 μmol), employing NEt3 (23 μL, 168 μmol) as base as outlined for Example 1, gave the title compound (25 mg, 42%): δH ((CD3)2SO)=1.30–1.40 (m, 2H), 1.50–1.60 (m, 4H), 2.90 (t, 4H), 7.15 (s, 1H), 7.60 (d, 1H), 7.90–8.00 (m, 2H); m/z (ES+)=361.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[C:13](F)=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1>CN(C=O)C.O>[Br:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([F:21])=[CH:14][C:13]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A 0° C. mixture of 2-chloro-4-hydroxypyridine (817 mg, 6.30 mmol) in DMF (30 mL) was treated with NaH (60% in mineral oil, 277 mg, 6.93 mmol), stirred for 1 h, treated with 5-bromo-2,4-difluoronitrobenzene (1.50 g, 6.30 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine (1.16 g, 53%). MS (ESI) m/z: (M+H+): 348.9.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C(Cl)(Cl)Cl>[C:16]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-hydroxysuccinimide (NAS) (1.15 g, 10.0 mmol) and triethylamine (1.53 ml) in chloroform (15 ml), acryloyl chloride (0.99 g, 11.0 mmol), cooled at 0° C., was added dropwise, under mechanical stirring, over a period of 30-min. After an additional stirring of 20 min at 0° C., the solution was washed with ice-cold water (8 ml for 2 times), dried on Na2SO4 and then filtered. 2,5-Di-tert-butylhydroquinone (0.5 mg) (polymerization inhibitor) was added to the chloroform solution, which was concentrated to a volume of 3 ml, using a rotary evaporator and filtered. Ethyl acetate (3 ml) and n-hexane (2 ml) were slowly added while stirring to the chloroform solution, which was left at 0° C. for several hours. The precipitate, a colorless solid, was separated by filtration and washed with an ice-cold solution of ethyl acetate/n-hexane (4/1) and then washed only with n-hexane.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([CH2:27][N+:28]#[C-:29])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>O.C(COC)OC>[CH3:16][S:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:29][N:28]=[CH:27]2)=[N:10][CH:11]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1ccc(N=Cc2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: CSc1ccc(-n2cncc2-c2ccccc2)nc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
N-benzal-5-(methylthio)pyridine-2-amine (200 g), tosylmethyl isocyanide (255 g), potassium carbonate (255 g), methanol (3 L) and dimethoxyethane (2 L) were refluxed overnight. The reactant was cooled to room temperature, 10 L water was added and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. The solvent was removed by filtration and reducing pressure. The crude product was purified by column chromatography to obtain the brown solid target compound (118 g, 50% yield). 1H-NMR (300 MHz, CDCl3): δ 2.52 (3H, s), 6.74-6.77 (1H, dd), 7.18-7.22 (3H, m), 7.30-7.33 (3H, m), 7.45-7.48 (1H, dd), 8.05-8.05 (1H, d), 8.38-8.39 (1H, d). LC-MS m/z: 268 [M++1].
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=1>O1CCCC1>[CH3:19][C:20]1[NH:24][N:23]=[C:22]([NH:25][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:21]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3ccccc32)n[nH]1

Procedure:
The named compound is prepared by substituting 5-methyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1345 gms. of 5-methyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22](Cl)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13].[OH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.[CH:37]([O:40][CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38]>C(N(CC)CC)C>[CH:37]([O:40][CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38].[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:34]4[CH2:35][CH2:36][CH:32]([OH:31])[CH2:33]4)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13]
Reactant: OC1CCNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCC(O)C4)nc32)c(F)cc1F
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To 550 mg of N,N-dimethylformamide were added 150 mg of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 100 mg of 3-hydroxypyrrolidine, and 100 mg of triethylamine. The solution was stirred at 70° C. for 30 minutes. The reaction solution was combined with 8 ml of diisopropyl ether, stirred, and allowed to stand. The supernatant was removed by decantation. To the remainder was added 2 ml of ethanol. The precipitate was collected by filtration and washed with ethanol and then with diisopropyl ether to give 156 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][O:14][C:15](=[O:22])[C@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH2:17].C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:22])[C@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:17][C:6]([C:5]1[S:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1)=[O:7]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Benzo[b]thiophene-2-carbonyl chloride (4.9 g, 25 mmol) was added to a stirred solution of L-leucine methyl ester (4.5 g, 25 mmol) and diisopropylethylamine (9 ml, 51 mmol) in DCM (200 ml). After stirring for 2 hours at room temperature, the mixture was poured into water and washed with brine and dried (MgSO4). Evaporation under reduced pressure afforded the title compound as a white solid, 7.6 g, 100% yield.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[CH2:24][O:25]C(C)=O>C1COCC1.CO>[CH2:16]([O:15][CH2:14][N:10]1[C:3]2[C:2]([O:25][CH3:24])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(C)=O
Reactant: Clc1ncnc2cc[nH]c12
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncnc2ccn(COCc3ccccc3)c12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.53 g, 10.0 mmol) in 30 mL of THF was added NaH (560 mg, 14.0 mmol, 60% in mineral oil) by portion under N2. After the mixture was cooled to 0° C., benzyl chloromethyl ether (1.71 mL, 13.0 mmol) was added. Then the mixture was stirred at RT for 1 h (monitored by TLC 40% EtOAc/Hex). 8 mL of anhydrous MeOH was added into the reaction mixture followed by NaH (400 mg, 10.0 mmol, 60% mineral oil) by portion. The resulting mixture was stirred at RT overnight. After being quenched with sat. NH4Cl, the mixture was extracted with EtOAc (3×). The organic layer was washed with sat.NaHCO3 (aq), brine, then dried (MgSO4) and concentrated. Silica gel chromatography (elution with 0-30% EtOAc/Hex) afforded product 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (2.36 g).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 2.84 g of tert-butyl 4(S)-(2(S)-hydroxymethyl-3-methylbutyl)-2,2-dimethyl-oxazolidine-3-carboxylate in 100 ml of dichloromethane is admixed at 0° C. successively with 1.41 ml of triethylamine and 0.76 ml of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. over 1 hour and subsequently concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.03 (gradient I).
Reaction SMILES: F[B-](F)(F)F.[H+].N[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[N:12][CH:13]=1.N([O:17][C:18]([CH3:21])(C)C)=O.C([O:24]CC)C>C(O)C>[C:18]([O:17][C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[N:12][CH:13]=1)(=[O:24])[CH3:21]
Reactant: CC(C)(C)ON=O
Reactant: CCOCC
Reactant: Nc1ccc(Cl)nc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: CC(=O)Oc1ccc(Cl)nc1
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
48% Aqueous tetrafluoroboric acid (40.5 mL) was added to the above-obtained 5-amino-2-chloropyridine (18 g) in ethanol (360 mL), and under cooling at −5° C., tert-butyl nitrite (23.5 mL) was added dropwise to the resultant mixture, followed by stirring for 20 minutes. Diethyl ether was added to the reaction mixture, and the precipitated product was recovered by filtration, followed by drying, to thereby give 6-chloropyridine-3-diazonium tetrafluoroborate (32 g, quantitative amount). The thus-obtained diazonium salt (32 g) in acetic anhydride (160 mL) was heated gradually to 90° C., and the mixture was stirred for 45 minutes, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was sequentially washed with water and saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (hexane-ethyl acetate), to thereby give 5-acetoxy-2-chloropyridine as a solid (10 g, 42%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][N:10]([CH3:16])[CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(O)CO>CC(O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:14][CH2:15][CH:11]([N:10]([CH3:16])[CH3:9])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1CCNC1
Reactant: Brc1cccc(I)c1
Agent: [Cu]I
Solvent: OCCO
Solvent: CC(C)O
Product: CN(C)C1CCN(c2cccc(Br)c2)C1
Temperature: 80 °C

Procedure:
1-Bromo-3-iodobenzene (1 eq, 3.53 mmol, 1 g), copper(I) iodide (0.05 eq, 0.177 mmol 0.034 g) and potassium phosphate tribasic carbonate (2 eq, 7.07 mmol, 1.51 g) are dissolved in 2-propanol (15 ml) under an inert atmosphere of nitrogen. Then, N,N-dimethylpyrrolidin-3-amine (2 eq, 7.07 mmol, 0.807 g) and ethylene glycol (2 eq, 7.07 mmol, 0.394 ml) are added and the reaction mixture heated at 80° C., overnight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:13][CH:14]=1.C(N(CC)C(C)C)(C)C.I[CH2:47][C:48]([NH2:50])=[O:49].O>CN(C)C=O>[NH2:50][C:48](=[O:49])[CH2:47][N:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][C:2]=2[F:1])[CH:14]=[CH:13]/[C:12]/1=[N:15]/[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)/N=c2/ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of benzyl {3-fluoro-4-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}carbamate (35.0 g, 69.0 mmol) in N,N-dimethylformamide (350 mL) were added N,N-diisopropylethylamine (15.6 mL, 89.6 mmol) and iodoacetamide (16.6 g, 89.6 mmol), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (28.0 g, 72%).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([S:13][CH2:14][CH2:15][OH:16])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32](Cl)=[O:33])([CH3:26])([CH3:25])[CH3:24].O>CCCCC>[C:23]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32]([O:16][CH2:15][CH2:14][S:13][C:7]([N:6]=[N:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:8])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:33])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)CC(C)(N=NC(C)(C)C)SCCO
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Solvent: O
Solvent: CCCCC
Solvent: c1ccncc1
Product: CC(C)CC(C)(N=NC(C)(C)C)SCCOC(=O)CCC(C)(C#N)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 6.5 grams (0.0264 moles) of 2-t-butylazo-2-(β-hydroxyethylthio)-4-methylpentane and 2.5 grams (.031 moles) of pyridine in 50 ml of pentane in a beaker was added 5.75 grams (.025 moles) of 4-t-butylazo-4-cyanovaleryl chloride dropwise while holding the reaction temperature at 25° ± 2° C. After the addition was complete, the reaction was stirred an additional 1/2 hour at 25° C, 50 ml of water added and the pentane layer separated. The pentane layer was successively washed with 25 ml of 10% HCl, 25 ml of water and 25 ml of 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a viscous tan liquid weighing 7.3 grams (66% yield). The product was purified by chromatographing it over alumina and eluting it with pentane. Evaporation of the pentane left a yellow viscous liquid whose infrared spectrum was in agreement with the structure of the desired product.
Reaction SMILES: [C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[CH:17]=2)=[C:6]1[OH:33])([CH3:4])([CH3:3])[CH3:2].C(C1[N:42](CC2C=CC(F)=C(C)C=2)[C:41](=O)C(C2NC3C=CC(NS(C)(=O)=O)=CC=3S(=O)(=O)C=2)=C1O)(C)(C)C>>[C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[C:17]=2[C:41]#[N:42])=[C:6]1[OH:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1C(O)=C(C2=CS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)N1CCC1CC1
Reactant: Cc1cc(CN2C(=O)C(C3=CS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)C2C(C)(C)C)ccc1F
Product: CC(C)(C)C1C(O)=C(C2=C(C#N)S(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)N1CCC1CC1

Procedure:
N-{3-[5-tert-Butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-2-cyano-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide was prepared from N-{3-[5-tert-butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (15c, R3=c-C3H5—(CH2)2) to afford 78 mg (49%) of I-27: LCMS RT 2.40 min, M+H.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].F[C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][C:15]=1[C:30]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)=[O:31]>>[CH2:21]([O:20][C:18]([C:17]1[CH:28]=[CH:29][C:14]([N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4]2)=[C:15]([C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[CH:16]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Product: CCOC(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 48.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (Intermediate 1A, 509 mg, 2.70 mmol) and benzyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (1.00 g, 2.57 mmol) were converted to the title compound (690 mg, 48%). 1H NMR (CDCl3, 1.5:1 mixture of amide rotamers) δ 8.35-8.28 (m, 1H), 8.18 (t, J=1.9 Hz, 1H), 7.76 (d, J=8.4 Hz, 0.5H), 7.70 (d, J=8.4 Hz, 0.5H), 7.50-7.45 (m, 2H), 7.43-7.31 (m, 3H), 7.23-7.07 (m, 3.5H), 6.90 (d, J=7.9 Hz, 0.5H), 5.42 (s, 2H), 4.76-4.54 (m, 1H), 4.47 (s, 1H), 4.16 (q, J=7.0 Hz, 2.5H), 3.64 (br s, 1.5H), 3.13-3.02 (m, 0.5H), 2.81 (t, J=6.1 Hz, 1H), 2.34 (s, 2H), 2.26 (s, 1H), 1.21 (t, J=7.0 Hz, 1H), 1.12 (t, J=7.2 Hz, 2H); MS(ESI+) m/z 558.4 (M+H)+.
Reaction SMILES: C([O-])(=O)CCC.[CH3:7][CH:8]([CH3:21])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:35][C:36](=[O:41])[CH2:37][CH2:38][CH2:39]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C.CCOC(C)=O.CCCCCCC>[CH3:7][CH:8]([CH3:21])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([O:19][CH2:39][CH2:38][CH2:37][C:36]([O:35][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:41])=[O:18])=[CH:12][CH:11]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: CCCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC#N
Product: CC(C)Cc1ccc(C(C)C(=O)OCCCC(=O)OCc2ccccc2)cc1
Temperature: 90 °C

Procedure:
Benzyl 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoate was synthesized from benzyl-4-bromo)butanoate, 2-[4-(2-methylpropyl)phenyl]propanoic acid and potassium carbonate. To a solution of benzyl-4-bromobutanoate (2.0 g, 7.8 mmol) in acetonitrile (20 ml) at ambient temperature was added potassium carbonate (1.13 g, 8.2 mmol) and 2-[4-(2-methylpropyl)phenyl]propanoic acid (1.6 g, 7.8 mmol). The reaction was heated to 90° C. for 18 hours and monitored by TLC (4:1 heptane:EtOAc) The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was partitioned between water and EtOAc and the organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with heptane:EtOAc (4:1, v:v) and isolated as a clear, colorless oil (2.5 g, 84% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 7.30-7.46 (5H, m), 7.02-7.23 (4H, m), 5.11 (2H, s), 3.99-4.21 (2H, m), 3.68 (1H, q, 7.2 Hz), 2.43 (2H, d, 7.2 Hz), 2.27-2.39 (2H, m), 1.73-2.04 (3H, m), 1.48 (3H, d, 7.2 Hz) 0.89 (6H, d, 6.6 Hz).