Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([NH:23][CH:24]=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH:24]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:23]=1
Reactant: O=CNCCc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: C1=NCCc2ccccc21
Temperature: 180 °C

Procedure:
A 250 mL round bottom flask equipped with stir bar, reflux condenser, and an addition funnel is charged with phosphorus pentoxide (7.07 g) and polyphosphoric acid in a 10.5:1 weight ratio. The mixture is stirred and heated at approximately 180° C. for about 1 hour, then cooled to approximately 150° C. The cooled, crude phenethylformamide prepared as described above is added dropwise to this mixture. On complete addition the reaction is heated and stirred at approximately 170° C. overnight. The mixture is cooled to room temperature and diluted with water (300 mL), washed with diethyl ether (150 mL) and cooled in an acetone/dry ice bath while the pH is adjusted to 9 with saturated potassium hydroxide. The aqueous solution is extracted with ether (3×150 mL) and the pooled organics are dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an oil that is further purified via Kugelrohr distillation (70° C., 1 mm Hg) to give the compound of formula 2.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH:18]=[O:19])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Zn]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH:18]([OH:19])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:17]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: O=CC1(c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)C1(c2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
A mixture of zinc dust (4.0 g, 61.2 mmol), ethyl bromoacetate (6.5 mL, 58.3 mmol) and 1-(p-chlorophenyl)-cyclopropanecarboxaldehyde (10.0 g, 55.4 mmol) in toluene is stirred at 70° C. for 45 minutes, cooled with an ice-water bath, treated with 100 mL of 10% sulfuric acid, stirred at room temperature for one hour, and diluted with ethyl acetate. The organic phase is separated, washed sequentially with 10% sulfuric acid, water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Chromatography of the oil using silica gel and a 9:1 to 7:3 hexanes/ethyl acetate gradient gives the title product as a colorless oil (11.3 g, 76%) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[H-].[Na+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CN(C=O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([O:12][CH:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][N:2]([CH3:1])[CH2:11]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: CN1Cc2ccccc2C(O)C1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2C(Oc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,2,3,4-tetrahydro-2-methyl-4-isoquinolinol (3.0 g, 0.018 mole) in dry DMF (15 ml) is added dropwise under nitrogen to a suspension of sodium hydride 50% (98%) (1.1 g, 0.022 mole), previously washed with hexane, in dry DMF (25 ml). The mixture is warmed to 60° C., at which time a solution of 4-fluorobenzonitrile (2.2 g, 0.018 mole) in dry DMF (15 ml) is slowly added. The reaction mixture is stirred at room temperature for 16 hours.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:26][CH3:27])[N:7]=1>Cl.C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:26][CH3:27])[N:7]=1
Reactant: COc1cc(NS(=O)(=O)N2CCC3(CC2)OCCO3)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-{2-[(2,3-Difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonamide (the product of step ii) (0.85 g) was heated to 50° C. in a mixture of 2 M aqueous hydrochloric acid (17 mL) and THF (17 mL). After 24 h, the reaction was allowed to cool to room temperature then diluted with ethyl acetate, the layers separated and the organic material washed with saturated aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to afford the subtitle compound as a yellow oil. Yield: 0.83 g
Reaction SMILES: [C:1]([NH:3][C:4]([N:6](C#N)[CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])=[NH:5])#[N:2].[CH3:19]N>C(O)C>[C:1]([N:3]=[C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])[NH:5][CH3:19])#[N:2]
Reactant: Cc1[nH]cnc1CSCCN(C#N)C(=N)NC#N
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Reaction time: 47 h

Procedure:
N,N'-Dicyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (527 mg) was added to a solution of CH3NH2 in ethanol (40%, 3.1 g) and stirred for 47 hrs. at room temperature. After concentration under a reduced pressure, the residue was triturated with CH3CN. The insuluble starting material was filtered off and the filtrate was concentrated under a reduced pressure and chromatographed on SiO2 [eluant: CH3CN-CH3OH (4:1)]. The resulting crude product was purified by preparative thin layer chromatography [SiO2, CH3 --COOC2H5 --CH3OH-- 28% NH3 (aq) (10:1:1)] and recrystallized from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (1.0 mg). m.p. 135°-137° C.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1ccncc1
Reactant: CN(C(=O)OCc1ccccc1)C1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(C(=O)OCc1ccccc1)C1CCCN(c2ccncc2)C1
Yield: 77 %

Procedure:
A mixture of benzyl methyl(piperidin-3-yl)carbamate (6.32 mmol, 1.0 eq.), 4-brompyridine HCl (2.5 g, 12.64 mmol, 2.0 eq.) and DIPEA (5.7 ml, 31.6 mmol, 5.0 eq.) in n-butanol (40 ml) was refluxed for 24 hours. The reaction mixture was concentrated and the residue was taken up in DCM (200 ml) and washed with sat. NaHCO3 solution (3×100 ml), water (100 ml) and sat. NaCl solution (100 ml). The org. phase was then dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 5% MeOH in DCM). Yield: 77% (1.6 g, 4.92 mmol)
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17](=[O:49])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH2:47]C)=[O:19].[Na]>O>[NH2:16][C:17](=[O:49])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([O:33][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19]
Reactant: ClCCN1CCOCC1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OCCN3CCOCC3)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
In a flask containing 10 ml of dimethylformamide is added with stirring 133 mg. of 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3) and 231 mg. of CsCO3 and 300 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-ethyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The slurry is heated to 60° C. until a solution formed. Heating is continued overnight until reaction is complete. 20 ml of H2O is added to the flask and the organic soluble phase is extracted with three 20 ml. portions of ethyl acetate. The ethyl acetate solution is washed with water and dried over Na2SO4.
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]#[CH:22])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:9]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]1[O:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:22]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2ncccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.14 g (14.4 mmol) sample of 2-iodo-3-hydroxypyridine (Lancaster Chem. Co.) was dissolved in 5 mL of DMF, and (Ph3P)2PdCl2 (0.34 g, 0.50 mmol), CuI (0.371 g, 1.98 mmol) and triethylanine (1.80 mL, 13.2 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g (11.0 mmol) of the compound from step 3a above, dissolved in 5 mL of DMF, was added carefully. The mixture was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether and filtered. The solution was washed with 10% NaOH, 50% brine, dried over MgSO4, and the solvent Awas removed. The residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 620 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.73 (s, 9H), 1.85-2.30 (m, 4H), 3.05-3.22 (m, 2H), 4.42 (m, 1H), 6.78 (s, 1H), 7.16 (dd, 1H), 7.68 (dd, 1H), 8.48 (dd, 1H); MS m/z: 289 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].Cl.[CH2:22](O)[CH3:23]>>[CH3:3][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:22][CH3:23])=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)c1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2nc3sc(C(C)C)cc3c(=O)n2c1
Temperature: 128 °C

Procedure:
A cooled suspension of 1.4 g (0.00486 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-7-carboxylic acid (Example 18) in 150 ml of ethanol is saturated with hydrogen chloride. The mixture is stirred and refluxed in a wax bath at 128° C. for eighteen hours under nitrogen. The ethanol is evaporated in vacuo to give 0.43 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, ethyl ester; mp 122°-123° C. after recrystallization from absolute ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:8]([OH:10])=[N:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1cccnc1C(=O)O
Product: Oc1ncnc2cccnc12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
3-Aminopicolinic acid (A-1) (30 g, 217 mmol, 1.0 eq) is suspended in formamide (75 mL, 1.88 mol, 8.66 eq). The resulting mixture is stirred at 140° C. for 1 h and at 170° C. for 1 h and then at 180° C. for an additional 1 h. The mixture is cooled to RT and filtered. The filter cake is washed with water, and dried in vacuo to afford the product, pyrido[3,2-d]pyrimidin-4-ol (A-2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12](O)([CH3:14])[CH3:13]>OS(O)(=O)=O>[CH:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=1)([CH3:14])[CH3:13]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5,6-dichloro nicotinic acid (12.2 g, 63.5 mmol) in isopropanol (70 mL), H2SO4 (4 mL) is added dropwise. The mixture is stirred at 80° C. for 16 h before it is cooled to rt and concentrated in vacuo. The residue is dissolved in dioxane (100 mL) and concentrated again. The crude product is purified by CC (heptane:EA 1:3) to give 5,6-dichloro nicotinic acid isopropyl ester (9.29 g) as a pale beige oil; LC-MS: tR=1.33 min, [M+1]+=233.94.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]1([C:32]2[N:37]=[C:36]3[NH:38][CH:39]=[C:40]([CH:41]=O)[C:35]3=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:41]/[C:40]3[C:35]4[C:36](=[N:37][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:33][CH:34]=4)[NH:38][CH:39]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1c[nH]c2nc(-c3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(-c5ccccc5)ccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.026 g, 0.075 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.013 g, 0.059 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.019 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[CH:6]3[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:23]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C:6]3([CH3:23])[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (745 mg, 2.53 mmol), DMSO (10 ml), iodomethane (0.189 ml, 3.03 mmol). The suspension was cooled to 0° C. and sodium 2-methylpropan-2-olate (292 mg, 3.03 mmol) was added. The reaction was removed from the ice-bath and stirred at 20° C. for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate 3 times and the organic layer washed with saturated NaCl. The organic layer was collected, dried with Na2SO4, filtered and the filtrate concentrated in vacuo to furnish a light-brown solid. The solid was washed with a small amount of ethanol followed by diethyl ether to afford 2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (641 mg, 2.228 mmol, 82% yield) as white solid. MS [M+H] found 309.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[OH:9].[CH:20]([C:22]1[C:23]([C:27]([NH:29][CH3:30])=[O:28])=[N:24][NH:25][CH:26]=1)=O.[BH3-]C#N.[Na+]>ClCCCl>[OH:9][CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:20][C:22]1[C:23]([C:27]([NH:29][CH3:30])=[O:28])=[N:24][NH:25][CH:26]=1
Reactant: Nc1ccccc1C(O)c1cccc2ccccc12
Reactant: CNC(=O)c1n[nH]cc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)c1n[nH]cc1CNc1ccccc1C(O)c1cccc2ccccc12
Reaction time: 5 h
Yield: 3.6 %

Procedure:
To a solution of product (5-B) (0.4 g 1.6 mmol) in DCE (20 mL) was added product (3-C) (0.25 g, 1.6 mmol) at rt under argon. The reaction was stirred for about 5 h, and then NaBH3CN (0.5 g, 8 mmol) was added and stirred overnight. The reaction was quenched by saturated NH4Cl (20 mL) and extracted with DCM/MeOH (20:1 v/v, 20 mL×2). The combined organic phases were dried over Na2SO4 and concentrated and purified by Prep-HPLC to give compound 4 (22 mg, 5%) as a white solid. 1H NMR (300 MHz, d-DMSO): δ 13.04 (br, 1H), 8.14-7.32 (m, 9H), 7.04-6.36 (m, 4H), 5.98-5.85 (m, 2H), 4.47 (d, 2H), 2.72 (d, 3H). LC-MS (M+H)+=387. 1H-NMR (in DMSO), LC-MS, MS, and HPLC (column: Thermo, 2.4 μm, 4.6×100 mm; mobile phase: H2O (0.05% TFA)-ACN (0.05% TFA), ACN from 10% to 100% in eight minutes; total flow rate: 1.0 mL/min) spectroscopy experiments were conducted to provide the data in FIGS. 3A-3C and FIGS. 4A-4B for compound 4.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OC)[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]1([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:5]1[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]1[CH2:12][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 168.3 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (400 mg, 1.05 mmol), 6-mercapto-purine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[C:7]([NH:17][C@H:18]([C:23]([OH:25])=O)[CH2:19][CH:20]([CH3:22])[CH3:21])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[BH4-].[Na+]>CO>[CH2:19]([C@H:18]([NH:17][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C@H:23]([OH:25])[CH2:2][Cl:1])[CH:20]([CH3:21])[CH3:22]
Reactant: O=C(CCl)CCl
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@H](O)CCl
Yield: 117.8 %

Procedure:
To a solution of N-Cbz-leucine chloromethyl ketone (2.0 g) in 20 mL of methanol was added, at 0° C., 1.0 g of sodium borohydride and the mixture was stirred at ambient temperature for 24 h. The solution was concentrated under reduced pressure and the residue partitioned between 20 mL of saturated aqueous NH4Cl and 500 ml of diethyl ether. The organic fraction was separated, dried over MgSO4 and concentrated in vacuo and the residue purified by silica gel chromatography to yield 1.8 g of white solid.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[N:16]1([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27]C(N)=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:3]([NH:2][CH:4]=[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][NH:7][C:6]3=[O:15])=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Solvent: Cc1ccccc1
Product: O=C1NCc2ccccc2C1=CNc1ccc(CCN2CCCC2)cc1
Temperature: 110 °C
Yield: 40.7 %

Procedure:
A mixture of 0.400 g (1.98 mmol) of (4E)-4-[(dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone and 0.414 g (2.18 mmol) of 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine in 4 mL of PhCH3 is heated at 110° C. for 2.5 h. The reaction is placed in a freezer and the precipitated material is collected, washed with cold PhCH3(2×) and Et2O and dried in vacuo to give 0.280 g (41%) of gold crystals: mp 169-173° C. (dec); 1H NMR (DMSO-d6) δ 11.4 (d, 1H, J=11.8 Hz), 8.01 (d, 1H, J=11.8 Hz), 7.63 (m, 2H), 7.16 (s, 4H), 7.07 (m, 2H), 4.40 (s, 2H), 2.60 (m, 4H), 2.50 (m, 2H), 1.67 (s (br), 4H); HRMS (ESI) m/e calcd for C22H25N3O 348.20704. found 348.20588 (M+H)+1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][O:11][CH3:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][O:11][CH3:12])[CH2:9][CH2:8][N:7]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCC1(C(=O)OC)CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC1(C(=O)OC)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a stirred mixture of 3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (140 mg, 0.81 mmol), triethylamine (112 μl, 0.82 mmol) and cesium carbonate (263 mg, 0.81 mmol) in acetonitrile (2 ml) was added tert-butyl bromoacetate (119 μl, 0.81 mmol) slowly. The mixture was stirred for 15 minutes, filtered and concentrated. The residue was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate and hexanes (1:2) provided 118 mg (51%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[CH:7]=1)[CH3:2].N1C=CC=CC=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-aminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.084 g, 0.24 mmol) and pyridine (2.0 mL) in CH2Cl2 (2.5 mL) was added 4-chlorobenzoyl chloride (0.04 mL, 0.29 mmol), and the reaction was stirred for 30 minutes at room temperature. The mixture was partitioned between CH2Cl2 and 1N aqueous HCl, and the organic layer was separated and washed twice with 1N aqueous HCl. The organic layer was dried and concentrated, resulting in the formation of a white precipitate. The precipitate was filtered off, and the filtrate was concentrated to give the title compound.