Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1.[C:25]([Si:29]([CH3:45])([CH3:44])[O:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/B1OC(C)(C)C(C)(C)O1)([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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>[Si:29]([O:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:44])[CH3:45]
Reactant: CC1(C)OB(/C=C/CCO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C)CCC2)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)c1nc(/C=C/CCO[Si](C)(C)C(C)(C)C)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 160 °C
Yield: 99.7 %

Procedure:
To a solution of compound 324 (0.10 g, 0.25 mmol) in dioxane (2 mL) was (E)-tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyloxy)silane (0.115 g, 0.50 mmol), followed by K2CO3 (0.069 g, 0.50 mmol) and water (0.40 mL). The resulting mixture was degassed with nitrogen and Pd(PPh3)4 (0.023 g, 0.02 mmol) was added. The mixture was heated in microwave reactor at 160° C. for 20 min. The mixture was diluted with EtOAc, and filtered through celite. The organic layer was concentrated, washed with water, dried over anhydrous Na2SO4 and concentrated again. The residue was purified using PL-Thiol MP SPE tube to provide compound 47A (0.126 g, 99%). LCMS (+ESI) m/z 506.4 [M+H]+.
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH3:47][O:48][CH2:49][CH2:50][CH2:51][NH2:52].[BH3-]C#N.[Na+]>>[CH3:47][O:48][CH2:49][CH2:50][CH2:51][NH:52][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1
Reactant: COCCCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCCNCc1ccc(B(O)O)s1
Yield: 40.9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(methyloxy)propyl]amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 7.6 mg of the title compound (9%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][CH2:2][CH2:3][O:4][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.29 ml of 2-bromoethanol was dissolved in 27.8 ml of dry dichrolomethane, and 7.21 ml of dihydropyran and then 48.1 mg of dry p-toluenesulfonic acid were added thereto. The mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was partitioned with 150 ml of chloroform and 75 ml of a 4% sodium hydrogen-carbonate aqueous solution. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (20/1). The product-containing fractions were put together, and the solvent was distilled off under reduced pressure to obtain 5.4 g of 2-bromo-1-(2-tetrahydropyranyloxy)ethane as a oily substance.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:37])[CH2:7][CH:8]([S:33][C:34](=O)C)[CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10]1.CI>CO>[CH3:4][O:5][C:6](=[O:37])[CH2:7][CH:8]([CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10]1)[S:33][CH3:34]
Reactant: COC(=O)CC(SC(C)=O)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)CC(SC)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 0.75 h
Yield: 98.6 %

Procedure:
Sodium methoxide (28% in methanol) (0.050 mL, 0.22 mmol) was added to a suspension of the product from step 11b (0.085 g, 0.18 mmol) in methanol (1.5 mL) at room temperature. The reaction turned clear and was stirred for 45 minutes, and then methyl iodide (0.05 mL, 0.80 mmol) was added. The reaction was stirred an additional 45 minutes, quenched with aqueous ammonium chloride, concentrated to remove the methanol, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with magnesium sulfate, and concentrated to give 3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-3-methylsulfanyl-propionic acid methyl ester (0.08 g, 99%) as an oil. MS found: (M+H)+=451.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].CC(O)=O.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[CH:29]1([CH2:32][NH:1][C:2]2[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[NH:12][C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH3:15])[CH2:31][CH2:30]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(S(C)(=O)=O)c1N
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(S(C)(=O)=O)c1NCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of (S)-tert-butyl 1-(2-amino-3-(methylsulfonyl)phenylamino)-1-oxopropan-2-ylcarbamate (prepared in example 51) (440 mg, 1.23 mmol), glacial AcOH (0.43 mL, 7.4 mmol) and cyclopropanecarbaldehyde (0.18 mL, 2.5 mmol) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (780 mg, 3.7 mmol) and stirred at rt under N2 for 18 h. The reaction mixture was diluted with EtOAc, washed with water, sat. aq sodium bicarbonate solution, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel column using 10 to 20% gradient of EtOAC:DCM (1:1) in DCM as eluent to give (S)-tert-butyl 1-(2-(cyclopropylmethylamino)-3-(methylsulfonyl)phenylamino)-1-oxopropan-2-ylcarbamate: LC-MS (ESI) m/z 412.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:16]([N:17](C(C)=O)[C:18]([CH3:20])=[O:19])=[C:15]([C:24]#[N:25])[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([NH:17][C:18]([CH3:20])=[O:19])=[C:15]([C:24]#[N:25])[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(=O)N(C(C)=O)c1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Yield: 77.6 %

Procedure:
A stirred mixture of 0.32 gram (8.6×10-4 mole) of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-cyano-5-bis- (methylcarbonyl)aminopyrazole, 10 mL of water, and 10 mL of ethanol was heated at reflux for four hours. The mixture was cooled, and most of the ethanol was removed by distillation under reduced pressure. The aqueous pot residue, which contained a solid, was diluted with water, and the mixture was filtered. The filter cake was dried to yield 0.22 gram of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-cyano-5-methylcarbonylaminopyrazole. The rmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][N:33]([CH3:36])[C:32](=[O:37])[CH:31]=1>>[CH3:26][C:23]([CH3:27])([CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:35]=[CH:34][N:33]([CH3:36])[C:32](=[O:37])[CH:31]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[C:24]#[N:25]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: Cn1ccc(Br)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 2 tR=1.103, m/z=470.4; 1H NMR (CDCl3) 1.26 (s, 3H), 1.41 (s, 3H), 1.49 (d, 3H), 2.09 (s, 2H), 2.24 (m, 1H), 2.53 (m, 2H), 2.88 (m, 1H), 3.56 (s, 3H), 5.59 (m, 1H), 6.38 (d, 1H), 6.78 (s, 1H), 6.84 (d, 2H), 7.19 (m, 2H), 7.31 (m, 6H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][O:13][C:14]2=[O:19])([O-])=O.C(=O)(O)[O-].[Na+].O>C1COCC1.CCOC(C)=O>[NH2:6][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][O:13][C:14]2=[O:19]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2c(=O)occc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Tin(II) chloride dihydrate (41.9 g, 185.7 mmol) was added to a stirred solution of 5-nitro-1H-isochromen-1-one (7.1 g, 37.1 mmol) in anhydrous THF (120 mL). The reaction mixture was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc (400 mL) and treated with saturated aqueous sodium bicarbonate to pH=10. Water (100 mL) was added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×150 mL) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to yield 5-amino-1H-isochromen-1-one (5.8 g, 36.0 mmol, 97%) as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Br[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:26]1=[O:34]>C(#N)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:23][CH2:24][N:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[O:27][C:26]3=[O:34])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1oc2ncccc2n1CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1oc2ncccc2n1CCN1CCN(c2ccccc2)CC1

Procedure:
In a round-bottomed flask under an argon atmosphere, surmounted by a condenser, 2.43 g (15 mmol) of 1-phenylpiperazine and then 2.61 cm3 (15 mmol) of diiso-propylethylamine are added to a solution of 2.43 g (10 mmol) of 1-(2-bromoethyl)-1H-oxazolo [5,4-b]pyrdin-2-one in acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.[Mg].[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>Cl.C(CC(=O)C)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:10])[CH2:13][CH:12]2[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:21][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Fc1cccc(Br)c1
Reactant: C1CCOC1
Agent: [Fe]
Agent: Cl
Agent: [Mg]
Solvent: CC(=O)CC(C)=O
Product: CCCC1CCC(CC(=O)c2cccc(F)c2)CC1
Reaction time: 1 h

Procedure:
Grignard's reagent prepared from 3-fluorobromobenzene (110 mmol), magnesium (110 mmol), and 100 ml of tetrahydrofuran (hereinafter referred to as THF) was added dropwise to a mixture prepared by adding iron acetylacetone (5 mmol) and 300 ml of dried toluene to the acid chloride (100 mmol) at a temperature lower than -50° C. and stirred for 1 hour at the same temperature. The reaction product thus obtained was added in 200 ml of 6M hydrochloric acid and then extracted with toluene (100 ml×2). Extract was dried with anhydrous magnesium sulfate, the solvent was distilled off, and the residue thus obtained was recrystallized from 50 ml of ethanol to obtain 2-fluoro-4-(1-oxo-2-(4-propylcyclohexyl)ethyl)benzene (75 mmol).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1.CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCOc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-butoxyphenyl)pyridin-2-amine (690 mg) in THF (dry) (5 ml) was added to a suspension of NaH (60%, 569 mg) and 2-chloroethanesulfonyl chloride (0.893 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc, and then recrystallized from IPE-EtOH to give the title compound (502 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Nc2nccs2)cc1
Reactant: ClCCN1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(N(CCN2CCCC2)c2nccs2)cc1

Procedure:
A solution of 1.0 g (5.2 mmol) of N-(4-fluorophenyl)thiazol-2-amine in 25 mL of THF was treated with 10.3 mL (10.3 mmol) of a 1.0 M solution of NaHMDS in THF and 0.88 g (5.2 mmol) of 1-(2-chloroethyl)pyrrolidine hydrochloride and heated at reflux for 18 h. The reaction mixture was poured into 250 mL of EtOAc and extracted thrice with 1 M aqueous HCl. The combined acidic extracts were brought to pH 12 with a 10% (w/v) solution of Na2CO3 and extracted five times with CHCl3. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography eluting with a linear gradient of neat EtOAc to 20% MeOH in EtOAc to deliver the desired compound. MS (M+H)+ 292.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:60]=[CH:59][C:51]([C:52]([O:54]C(C)(C)C)=[O:53])=[C:50]([OH:61])[CH:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:60]2[CH:48]=[CH:49][C:50]([OH:61])=[C:51]([CH:59]=2)[C:52]([OH:54])=[O:53])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1O
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl 4-amino-2-hydroxybenzoate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].Cl.[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]2[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]2)[S:7][C:8]=1[C:16]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]
Reactant: COC1CCNCC1
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1CCN(CC(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
Compound 531 (120 mg, 0.300 mmol) and 4-methoxypiperidine hydrochloride (139 mg, 0.900 mmol) were suspended in THF (4 mL), and triethylamine (0.140 mL, 0.990 mmol) was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=49:1), followed by reslurrying with a mixed solvent of diisopropyl ether and diethyl ether to afford the entitled Compound 545 (96.0 mg, 74%) as a white solid.
Reaction SMILES: Cl[CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C.O>O1CCCC1>[NH:8]([CH:2]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5])[C:9]([CH3:10])=[O:11]
Reactant: c1nc[nH]n1
Reactant: CC(=O)NC(Cl)C(Cl)(Cl)CCl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NC(n1cncn1)C(Cl)(Cl)CCl
Yield: 66 %

Procedure:
3.6 gm of N-(1,2,2,3-tetrachloro-n-propyl)-acetamide were dissolved in 30 ml of tetrahydrofuran, and, while stirring, the resulting solution was added dropwise to a solution of 1.05 gm of 1,2,4-triazole and 1.8 gm of triethylamine in 20 ml of tetrahydrofuran. Subsequently, the reaction mixture was stirred for 2 hours at room temperature, then water was added, and the tetrahydrofuran was distilled off in vacuo. The oil thus obtained as a residue crystallized after some time and was recrystallized from methanol/water, yielding 2.7 gm of the compound of the formula ##STR5## having a melting point of 135° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:20])[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:20])[C:9]3[C:14]([S:15](=[O:18])(=[O:19])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)#[N:2]
Reactant: NC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
3-Carbamoylthioxanthone-10,10-dioxide (32.5 g) was dissolved in dimethyl formamide (ca. 1 litre) and cooled to -10° C in a solid carbon dioxide ethanol bath. Thionyl chloride (80 ml) was then added dropwise over 0.5 hour, maintaining the internal temperature at -5° to -10° C. Stirring was continued at this temperature for a further 2 hours. The reaction mixture was then poured into ice-water. The precipitated solid was filtered off, washed well with water, and dried at 100° C. The resulting 3-cyanothioxanthone-10,10-dioxide had a melting point of 282- 283° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:35](OC)=[O:36])=[N:4][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si](C(C)C)(C(C)C)C(C)C)[CH:19]=2)=[N:6][C:7]=1[NH:8][CH:9]1[C:17]2[C:12](=CC=C[CH:16]=2)CC1.[NH2:39]C1C(C(OC)=O)=NC(Cl)=NC=1NCC(C)C.C([Si](C(C)C)(C(C)C)[O:60][C:61]1C=CC=C([Sn](C)(C)C)C=1)(C)C>CN(C)C=O>[OH:24][C:20]1[CH:19]=[C:18]([C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:61](=[O:60])[N:8]3[CH2:9][CH:17]([CH3:12])[CH3:16])=[C:3]([C:35]([NH2:39])=[O:36])[N:4]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[Si](Oc1cccc([Sn](C)(C)C)c1)(C(C)C)C(C)C
Reactant: COC(=O)c1nc(Cl)nc(NCC(C)C)c1N
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc(NC2CCc3ccccc32)c1N
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Temperature: 100 °C
Yield: 58 %

Procedure:
Methyl 5-amino-6-(2,3-dihydro-1H-inden-1-ylamino)-2-(3-(triisopropylsilyloxy)phenyl)pyrimidine-4-carboxylate. Methyl 5-amino-2-chloro-6-(isobutylamino)pyrimidine-4-carboxylate. (0.285 g, 1.11 mmol) triisopropyl(3-(trimethylstannyl)phenoxy)silane (0.691 g, 1.67 mmol) and bisdichloro(triphenylphosphine) palladium (0) (0.311 g, 0.444 mmol) were combined in dimethyl formamide (4 mL) and heated to 100° C. The reaction was monitored via thin layer chromatography. Once starting materials were consumed, the solution was condensed under reduced pressure and purified using Biotage chromatography (0 to 40% EtOAc in hexanes) to afford the title compound (0.300 g, 58%). MS (ESI) m/z 473.6 [M+1]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([O:14][C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[NH2:41][C:42]1[CH:43]=[C:44]([S:48]([O:51][C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>C(Cl)(Cl)Cl>[CH:10]1[C:11]2[CH:12]([O:14][C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28]([NH:41][C:42]5[CH:43]=[C:44]([S:48]([O:51][C:52]6[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=6)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=5)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(N)c2)cc1
Reactant: O=C(Nc1ccc2ccc(C(=O)O)cc2c1)OC1c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(OS(=O)(=O)c2cccc(NC(=O)c3ccc4ccc(NC(=O)OC5c6ccccc6-c6ccccc65)cc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 104 mg (0.026 mmol) of compound 107 was added 6.5 mL of chloroform, 1.3 mL of thionyl chloride, and 100 μL of pyridine. The reaction was allowed to stir at ambient temperature for 3 hours and then all volatiles were removed in vacuo. The residue was stripped in vacuo from chloroform twice. To the resulting solid, suspended in 15 mL of chloroform was added 74 mg (0.028 mmol) of 4-methylphenyl 3-aminobenzenesulfonate (compound 5) and 27 μL (0.033 mmol) of pyridine as a solution in 1.5 mL of chloroform. The reaction was allowed to stir at ambient temperature for 16 hours, after which it was partitioned between ethyl acetate and 1 N HCl (aqueous). The organic layer was dried (magnesium sulfate), filtered, and the volatiles were removed in vacuo. The resulting residue was treated with diethyl ether. and the solid precipitate collected by vacuum filtration. This provided 110 mg of compound 108.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.C[NH:14]C1C=CC=CC=1>>[NH2:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: CNc1ccccc1
Product: Nc1ccc2ccccc2n1

Procedure:
6-Bromo-2-chloroquinoline (250 mg, 1.0 mmol) and N-methylaniline (2 mL) were heated at 120° C. for 16 hours. Extraction from 2M NaOH into DCM and drying on Na2SO4 gave the crude 2-aminoquinoline. This was converted, via Methods 3 and 5, to compound 205 (88 mg, 31%). [M−H]−=277.0 m/z. Activity: B