Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH3:20])=[C:15]([O:21][CH2:22][C:23]#[N:24])[CH:14]=[CH:13]2.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]=3[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[O:21][CH2:22][C:23]#[N:24]
Reactant: Cc1c(OCC#N)ccc2cc(-c3cc4ccccc4o3)ccc12
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3c(C)c(OCC#N)ccc3c2)oc2ccccc12
Yield: 31.4 %

Procedure:
Following the procedure described in Step 2 of Example 1, 2-{[6-(1-benzofuran-2-yl)-1-methyl-2-naphthyl]oxy}acetonitrile (1.15 g, 3.67 mmol) was acylated with valeryl chloride (0.52 mL, 4.4 mmol), in presence of tin (IV) chloride (0.52 mL, 4.4 mmol) in methylene chloride (15 mL). 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile was prepared. Purification by flash chromatography (Biotage apparatus) using 10-20% chloroform in hexane and 100% hexane and 0.5-5% ethyl acetate in hexane as eluants yielded the title compound as a yellow gum (0.458 g). 1HNMR (300 MHz, DMSO-d6): δ8.45 (s, 1H), 8.2 (d, 1H, J=7.7 Hz), 8.05 (t, 2H, J=8.8 Hz), 7.95 (d, 1H, J=7.7 Hz), 7.75 (d, 1H, J=7.7 Hz), 8.65 (d, 1H, J=7.7 Hz), 7.4-7.5 (m, 2H), 5.35 (s, 2H), 2.75 (t, 2H, J=8.1 Hz), 2.55 (s, 3H), 1.5-1.6 (m, 2H), 1.1-1.25 (m, 2H), and 0.7 ppm (t, 3H, J=8.8 Hz).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution of benzyl 4-((6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (104; 2.20 g, 5.20 mmol) in dichloromethane (10 mL) was added TFA (3.4 g, 31.2 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to adjust the pH=9. The resulting mixture was then extracted with dichloromethane (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford benzyl 4-((6-aminopyridin-3-yl)methyl)piperazine-1-carboxylate 105 (1.50 g, 89%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[Cl:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[I-].[Na+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[Cl:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(NOCC1CC1)c1cc2c(ncn2CCCCCl)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCN(CCCCn2cnc3c(F)c(Nc4ccc(Br)cc4Cl)c(C(=O)NOCC4CC4)cc32)CC1
Yield: 73.1 %

Procedure:
A solution of 6-(4-bromo-2-chloro-phenylamino)-3-(4-chloro-butyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 18ee (10 mg, 0.018 mmol), sodium iodide (14 mg, 0.092 mmol), and 1-methyl-piperazine (10 μL, 0.092 mmol) are stirred at 85° C. for three hours. The reaction mixture is diluted with ethyl acetate and washed three times with water, washed twice with saturated aqueous potassium carbonate, dried (Na2SO4) and concentrated under reduced pressure to a yellow oil. Flash column chromatography (1:1 dichloromethane/methanol followed by methanol followed by 20:1 methanol/triethylamine) yields clean product (8 mg, 72%) as an off-white foam. MS ESI (+) m/z 607, 609 (M+, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.71 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.40 (dd, 1H), 4.38 (t, 2H), 3.62 (d, 2H), 2.45 (broad, 8H), 2.41 (t, 2H), 2.28 (s, 3H), 1.96 (m, 2H), 1.54 (m, 2H), 1.07 (m, 1H), 0.50 (d, 2H), 0.22 (d, 2H).
Reaction SMILES: C(=O)(OC)O[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:15][CH2:16][CH:17]1[CH2:19][CH2:18]1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[CH:17]1([CH2:16][NH:15][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=[CH2:3])[CH2:19][CH2:18]1
Reactant: NCC1CC1
Reactant: COC(=O)OC/C=C/c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CCO
Product: C=CC(NCC1CC1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (E)-cinnamyl methyl carbonate (0.73 g) in EtOH (8 mL) at RT under N2 was added (aminomethyl)cyclopropane (1 mL), triphenyl phosphite (0.096 g) and [Ir(COD)Cl]2 (0.051 g). The reaction mixture was stirred at 85° C. overnight, then cooled to RT. MP-TsOH resin (1.3 mmol/g, 9 g) and EtOH (30 mL) were added to the reaction and the resulting mixture stirred for 2 hr. The resin was filtered from the reaction mixture and thoroughly washed with EtOH. The isolated resin was then washed separately with ammonia (7 N in MeOH) and the filtrate was concentrated to an oil. The crude material was purified via column chromatography (10% then 15% EtOAc/hexanes) to give the desired product (0.13 g, 18%). 1H NMR (300 MHz, CDCl3) δ 0.045-0.092 (m, 2H), 0.42-0.49 (m, 2H), 0.92-1.02 (m, 1H), 2.33 (dd, 1H), 2.47 (dd, 1H), 4.21 (d, 1H), 5.08 (d, 1H), 5.19 (d, 1H), 5.88-5.99 (m, 1H), 7.23(m, 5H). MS APCI, m/z=188 (M+1). LC/MS 1.25 min., Method A.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[C:55]([O:57][CH3:58])[C:54]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:56]=[C:55]([O:57][CH3:58])[C:54]([C:59]2[CH:60]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=2)=[CH:53][N:52]=1
Reactant: COc1ncc(-c2cccc(N)c2)c(OC)n1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c(OC)n1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,4-dimethoxy-pyrimidin-5-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.010 g of product in 39% yield: LCMS (ESI) m/z 420 (MH+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[C:19](I)=[CH:18][CH:17]=[CH:16][N:15]=1.[I:21][CH3:22]>C1COCC1>[F:13][C:14]1[C:19]([CH3:18])=[C:22]([I:21])[CH:17]=[CH:16][N:15]=1
Reactant: CI
Reactant: Fc1ncccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1c(I)ccnc1F
Reaction time: 1 h
Yield: 88.4 %

Procedure:
n-Butyl lithium (1.6M hexane solution, 53.8 mL) was added to a solution of diisopropylamine (8.71 g) in THF (200 mL) at −10 C. After being stirred at the same temperature under nitrogen atmosphere for 1 hour, a solution of 2-fluoro-3-iodopyridine (18.3 g) in THF (70 mL) was added to the reaction mixture at −78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 1 hour. A solution of iodomethane (12.8 g) in THF (30 mL) was added to the reaction mixture at −78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was quenched with aqueous saturated ammonium chloride solution at 0 C and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through NH-silica and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19](=O)[CH3:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH:19]([N:23]([CH3:24])[CH3:22])[CH3:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(COc1ccc2c(-c3ccc(Br)cc3)nsc2c1)N(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
74 mg (0.20 mmol) 1-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propan-2-one were treated with 133 μM 2M(0.17 mmol) dimethylamine in THF and 60 μM (0.20 mmol) tetraisopropyl orthotitanate. The solution was stirred at RT for 3.5 h. The mixture was diluted with 2 ml ethanol and 15 mg (0.2 mmol) NaCNBH3 were added, and stirring was continued over night. NaHCO3 and EtOAc were added, the inorganic phase extracted with EtOAc. The organic phases were washed with water and brine, dried over Na2SO4 and evaporated. Column chromatography with CH2Cl2:MeOH 9:1 gave {2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-1-methyl-ethyl}-dimethyl-amine as colorless oil, MS: 391 (MH+, 1Br).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=O.Cl.[NH2:22][OH:23].[OH-].[Na+]>C1COCC1>[OH:23]/[N:22]=[CH:1]/[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(/C=N/O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (400 mg, 1.44 mmol) and hydroxylamine hydrochloride (200 mg, 2.86 mmol) were combined in a flask with 25 mL of THF and 25 mL of 1 N NaOH solution. Stirred at rt for 1 h. Then added dichloromethane (50 mL) and extracted the aqueous layer 3 times with DCM (50 mL), dried over Na2SO4 and concentrated. Purified the oxime via MPLC (DCM/MeOH+1% NH4OH) to give title compound (200 mg, 47% yield) as a tan solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][P:8]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.O.[OH-].[Li+]>C1COCC1.O>[CH2:19]([O:18][P:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of the compound of example 73 (8.66 g, 23.02 mmol) in THF (150 mL) was treated drop wise with a solution of lithium hydroxide-mono hydrate (1.97 g, 46.04 mmol) in water (150 mL). The reaction was complete after about 1 h, according to TLC analysis. Most of the solvent was evaporated. The residue was partitioned between water and ether. The organic phase was separated and the alkaline phase was extracted again with ether. It was next acidified with HCl (6M) to pH˜1 followed by several extractions with ethyl acetate. The recombined organic layer was dried over sodium sulfate, filtered, and evaporated to give the product as colorless oil. 1H-NMR(CDCl3, 400 MH: 1.88(m, 4H); 2.40(t, J=6.9 Hz, 2H); 4.97,4.96, 5.05(2dd, J1=11.8 Hz. J2=8.1 Hz, 4H); 7.35(m, 10H). 31P-NMR(CDCl3, 400 MHz): 33.15.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:3]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]2[N:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1.C1(C)C(C)=CC=CC=1.C(=O)(O)[O-].[Na+]>C(N(C(C)C)CC)(C)C.O.C(OCC)(=O)C.CO.C(N(CC)CC)C.ClCCl.C(OCC)(=O)C>[NH:43]1[C:44]2[C:39](=[CH:38][CH:37]=[C:36]([CH:33]3[CH2:34][CH2:35][N:30]([C:2]4[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[O:13])[C:3]=4[CH3:29])[CH2:31][CH2:32]3)[N:45]=2)[CH2:40][CH2:41][CH2:42]1
Reactant: c1cc2c(nc1C1CCNCC1)NCCC2
Reactant: Cc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 120 °C
Yield: 6 %

Procedure:
A mixture of 370 mg (0.88 mmoles) of (1,1-dimethylethyl) 3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy)carbonyl]alaninate and 1.0 g (1.79 mmoles) of 1,2,3,4-tetrahydro-7-(4-piperidinyl)-1,8-naphthyridine, tris (trifluoroacetate) (prepared according to Patents EP 1065207 or WO 0078317) in 1 ml of diisopropylethylamine is heated at 120° C. for 2 hours. Then 10 ml of xylene is added and the medium is taken to reflux for 4 hours. The reaction medium is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum and the residue is chromatographed on silicagel with a gradient of 100% ethyl acetate to a mixture of ethyl acetate-methanol-triethylamine-dichloromethane 50-10-10-50.32 mg (Yield=6%) of expected product is obtained and 200 mg (54%) of chlorinated starting product is recovered.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][N:12]=[C:7]2[NH:6][CH2:5][C:4]1=[O:22])[CH3:2].Br[C:24]1[C:25]([CH3:41])=[N:26][C:27]([C:30]2[N:34]=[CH:33][N:32]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[N:31]=2)=[CH:28][CH:29]=1.C(=O)([O-])O.[K+].O1CCCC1>Cl[Pd]Cl.O>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([C:24]3[C:25]([CH3:41])=[N:26][C:27]([C:30]4[N:34]=[CH:33][N:32]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][O:36]5)[N:31]=4)=[CH:28][CH:29]=3)=[CH:11][N:12]=[C:7]2[NH:6][CH2:5][C:4]1=[O:22])[CH3:2]
Reactant: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Reactant: CCN1C(=O)CNc2ncc(B3OC(C)(C)C(C)(C)O3)nc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)CNc2ncc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3C)nc21
Temperature: 55 °C

Procedure:
A portion of 1-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.95 equiv), potassium hydrogen carbonate (2.3 equiv), and PdCl2 Amphos2 (0.001 equiv) were treated with a mixture of tetrahydrofuran and water, and the reaction mixture was heated to 55° C. The reaction mixture was cooled and the organic layer was treated with activated carbon at ambient temperature and filtered. The filtrate was distilled to 70% of its original volume, cooled, treated with water, seeded, and treated with additional water. The solids were filtered and washed with tetrahydrofuran/water and dried to obtain 1-ethyl-7-(2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as a solid.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:16]([O:17]CC3C=CC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:25])[C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH2:1]([C:8]1[NH:9][C:10]2[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:25])[C:11]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c2[nH]c(Cc3ccccc3)nc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(O)c2[nH]c(Cc3ccccc3)nc12
Yield: 85 %

Procedure:
A solution of 2-benzyl-4-benzyloxy-7-methylbenzimidazole (3.0 g) in ethanol (400 ml) and 10% palladium-carbon (1.5 g) was hydrogenated at room temperature and pressure until uptake of hydrogen ceased. The mixture was filtered (celite), and the filtrate was evaporated to dryness in vacuo and recrystallized from ethanol-ether to afford the title compound (1.85 g), m.p. 204°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[CH:17](O)[CH2:16][N:15]([CH3:19])[C:14]2=[O:20])=[CH:4][CH:3]=1>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C@@H:13]3[C:14](=[O:20])[N:15]([CH3:19])[CH2:16][C@@H:17]3[C:4]=2[CH:3]=1
Reactant: CN1CC(O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Solvent: ClCCl
Product: CN1C[C@@H]2c3cc(Cl)ccc3Oc3ccccc3[C@@H]2C1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A mixture of 3 g (9.4 mmol) of 3-[2-(4-chlorophenoxy)phenyl]-4-hydroxy-1-methylpyrrolidine-2-one (compound XIIIb) and 40 g of polyphosphoric acid was stirred overnight at 110° C. After cooling down to room temperature, the resulting mixture was poured into 150 mL of an ice-water mixture. 100 mL of dichloromethane were added, and the organic phase was extracted. The aqueous phase was washed with 50 mL of dichloromethane. The organic phases were combined, washed with brine, and evaporated under vacuum. The crude product was purified by column chromatography to obtain 0.5 g of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (compound cis-VIb). Yield: 17.7%.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].N([O-])=[O:12].[Na+]>O.C([O-])([O-])=O.O.O.[Cu].[Cu+2]>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[NH2:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:12])[C:8]([OH:10])=[O:9]
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: [Cu]
Agent: NCCCC[C@H](N)C(=O)O
Solvent: O
Product: N[C@@H](CCCCO)C(=O)O
Reaction time: 6 h
Yield: 30 %

Procedure:
A suspension of L-lysine (0.931 g, 5.1 mmol) and CuCO3.Cu(OH)2 (1.24 g, 5.6 mmol) in water (15 ml) was heated under reflux for 5 minutes then cooled and filtered. The pH of the filtrate was adjusted to 4 with 2M H2SO4. A solution of sodium nitrite (0.70 g, 10 mmol) in water (5 ml) was added dropwise over 10 minutes and the mixture was strirred at 24° C. for 6 hours. Chelex 100 resin (40 g) was added to effect decomplexation. The resulting suspension was then filtered to give a solution of L-lysine (60%) and (S)-2-amino-6-hydroxyhexanoic acid 2 (30%). ##STR2##
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8](N[C@H](C(NCC(O)=O)=O)CS)=[O:9])[C:3]([OH:5])=[O:4].[O:21]=[C:22]([C@H:24]([CH2:26][C:27]1[CH:34]=[C:32]([OH:33])[C:30]([OH:31])=[CH:29][CH:28]=1)[NH2:25])[OH:23]>C(O)C(N)(CO)CO>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]([NH:25][C@@H:24]([CH2:26][C:27]1[CH:34]=[C:32]([OH:33])[C:30]([OH:31])=[CH:29][CH:28]=1)[C:22]([OH:23])=[O:21])=[O:9]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: NC(CO)(CO)CO
Product: N[C@@H](CCC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O)C(=O)O
Reaction time: 6 h

Procedure:
Glutathione and L-DOPA were incubated with a partially purified preparation of sheep kidney γ-glutamyl transpeptidase. γ-Glutamyl-DOPA was isolated from the incubation mixture by preparative ion exchange chromatography on a Dowex-1 (acetate) column. 6.14 of glutathione (0.02 mole) and 1.97 g of L-DOPA (0.01 mole) were dissolved in 200 ml of 1 M Tris (base) solution. 2.5 ml of γ-glutamyl transpeptidase solution (100 units/ml) were added and the flask was flushed with nitrogen to protect DOPA from oxidation and the mixture was incubated at 37° for 6 hours. L-γ-glutamyl-L-3,4-dihydroxyphenylalanine (γ-glutamyl-DOPA) was isolated by ion exchange chromatography as in Example 1. It emerges from the column when approximately 2 liters of the eluent passed through the column. Unreacted. glutathione, free glutamate and cysteinylglycine emerge from the column in earlier fractions.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21](CC3C=CC(OC)=CC=3)[C:20](=[O:32])[N:19]2[CH3:33])=[CH:11][C:10]=1[CH3:34])([CH3:7])[CH3:6])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:32])[N:19]2[CH3:33])=[CH:11][C:10]=1[CH3:34])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CNC(=O)N2C)cc1C

Procedure:
2-(4-{2-[1-(4-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (0.105 g, 0.217 mmole) is treated with tryethylsilane (0.064 g, 0.743 mmole) in TFA (8.0 mL) at room temperature for about 6 hours. After evaporating the solvents, the residue is purified using silica gel (0-50% acetone/hexane). Colorless oil (0.041 g, 51%). Mass [EI+] 365 (M+H)+, 729 (2M+H)+.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][C@H:22]4[C@@H:28]([F:29])[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>C(Cl)(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][C@H:22]4[C@@H:28]([F:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Fc1cc(O[C@@H]2CCNCC[C@@H]2F)c2nc(-c3nnc4ccccn34)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Enantiomer 2 of (cis)-tert-butyl 4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (Example 90, Step D; 0.119 g, 0.240 mmol) was dissolved in CHCl3 (2.4 mL). HCl (2.40 mL, 9.61 mmol, 4.0M Dioxane) was added and the mixture was stirred at ambient temperature for 3 hours. The mixture was filtered through a polypropylene filter and washed with CH2Cl2 and then Et2O, then slurried in hexanes and dried carefully in vacuo to provide 0.095 g of the desired product as a white solid (85%). MS ESI (+) m/z 396.1 (M+1) detected.