Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[C:10]([CH2:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:24])=[C:10]([CH2:15][C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)C(=O)Cc1nc(NC(=O)OC(C)(C)C)ccc1Br
Agent: [Pd]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: CCN(CC)C(=O)Cc1nc(NC(=O)OC(C)(C)C)ccc1C
Temperature: 25 °C

Procedure:
(5-Bromo-6-diethylcarbamoylmethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.116 g in dioxane (5 mL) was treated successively at RT with potassium carbonate (0.124 g), tetrakis(triphenylphosphine) palladium(0), 35 mg, and trimethylboroxine (38 mg) and then heated to reflux for 22 h. The mixture was cooled to RT, filtered and the filter cake washed with AcOEt. The filtrate was concentrated in vacuo, the residue purified by flash chromatography (heptane/AcOEt 1:1 to 1:4) to give (6-diethylcarbamoylmethyl-5-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (37 mg) as a colorless gum. MS (ESI): 322.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[C:17]1([CH2:23][N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:27]1[CH2:26][CH2:25][N:24]([CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:29][CH2:28]1)([O-:16])=[O:15]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1-c1ccccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1ccccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To a solution of 30.0 g (0.140 mol) of 2-amino-2′-nitrobiphenyl and 111.5 g (0.630 mol) of 1-(phenylmethyl)-4-piperidone in 1200 mL of dichloromethane were added a total of 140.5 g (0.630 mol) of sodium triacetoxyborohydride in batches whilst maintaining a reaction temperature of 0° C. and the mixture was then stirred for 14 hours at room temperature. It was made alkaline with sodium hydroxide solution, the dichloromethane phase was separated off, dried over sodium sulfate and concentrated by evaporation. The residue was digested with methanol, then filtered. The filtrate was evaporated down, the residue remaining was purified by chromatography on aluminium oxide (activity stage 3) using PE/EE 9/1 (v/v) as eluant. Corresponding fractions were combined, freed from solvent and used in the next step without further purification. Yield: 40.0 g (74% of theory).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:36]1[C:44]2[C:39](=[C:40]([C:45]3[CH:46]=[C:47]([NH2:54])[C:48]4[CH:49]=[N:50][NH:51][C:52]=4[CH:53]=3)[CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37]1>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:1]([N:3]1[C:7]([C:8]([NH:54][C:47]2[CH:46]=[C:45]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:39]=3[CH:38]=[CH:37][NH:36]4)[CH:53]=[C:52]3[C:48]=2[CH:49]=[N:50][NH:51]3)=[O:10])=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
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: CCn1nc(C)cc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h

Procedure:
1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (67.8 mg) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (168 mg) in DMF (750 μl) and DIPEA (150 μl). Reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg) in DMF (350 μl). Reaction mixture was left to stand at 22° C. for 16 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 ml) prior to application on to a preconditioned (methanol then chloroform) aminopropyl SPE cartridge (1 g). Product was eluted after 2 h with ethyl acetate:methanol (1:1, 3.2 ml), and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method B) gave the title compound.
Reaction SMILES: C1CN[C@@H](C(N[C@H](C(NC([C@@H]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)CCCN=C(N)N)=O)=O)CC2C=CC=CC=2)=O)C1.C(O)(=O)C>C(O)C(N)(CO)CO.Cl>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([NH2:30])=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: NC(N)=NCCC[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCCN1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h

Procedure:
An inhibitor sample is dissolved in a 0.05 M Tris-hydrochloric acid buffer solution (pH=7.8) to make the total volume to 400 μl. To this solution, 50 μl of a 2 mM S-2302 solution is added and the mixture is incubated at a temperature of 37° C. for 5 minutes in a constant temperature bath. Then, 50 μl of a 0.12 unit/ml human plasma kallikrein is added and the mixture is incubated at a temperature of 37° C. for 5 minutes. Thereafter, 50 μl of 50% acetic acid is added to terminate the reaction. The absorbance of the p-nitroaniline formed in the reaction mixture is measured at 405 nm. Thus, the concentration I50 (μmol) of the inhibitor sample, at which the absorbance is one half (i.e., 1/2) of that obtained in the absence of the inhibitor sample, is determined.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:26]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][CH:9]1[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2

Procedure:
tert-Butyl 1-benzyl-7-(propylsulfonamidomethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.628 g, 1.33 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil. Product was obtained as a brown oil (0.487 g, 1.31, 98%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1I
Reactant: COC(=O)CCC#Cc1ccc(Cl)cc1
Product: COC(=O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)nc12

Procedure:
Prepared from 6-chloro-2-iodo-3-pyridinamine (Description 14) and methyl 5-(4-chlorophenyl)-4-pentynoate (Description 2) according to the method of Description 4. 1H NMR (500 MHz, CDCl3) δ 8.20 (1H, br s), 7.56 (1H, d, J 8.4 Hz), 7.52 (2H, d, J 8.5 Hz), 7.47 (2H, d, J 8.5 Hz), 7.11 (1H, d, J 8.4 Hz), 3.61 (3H, s), 3.21 (2H, t, J 7.8 Hz), and 2.85 (2H, t, J 7.8 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][O:4][CH2:5][C:6]([F:9])([F:8])[F:7].[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>[Cu]>[F:7][C:6]([F:9])([F:8])[CH2:5][O:4][CH:3]1[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1([CH3:10])[CH3:1]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=COCC(F)(F)F
Agent: [Cu]
Product: CCOC(=O)C1C(OCC(F)(F)F)C1(C)C

Procedure:
2,2,2-Trifluoroethyl 2-methyl-1-propenyl ether (3.2 g) is combined, under nitrogen, with approx. 150 mg copper powder and heated to 130°. Ethyl diazoacetate (2.36 g) is very slowly added to the solution over 1.5 hr. The solution is then cooled and filtered, and the filtrate is washed with ether. The ether phase is distilled in vacuo to yield ethyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[C:20]([Cl:21])=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[C:22]1([N:28]2[C:32]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:31](=[O:38])[NH:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[Cl:6][C:7]1[C:20]([Cl:21])=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:35]3[CH2:34][CH2:33][C:32]4([N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][NH:30][C:31]4=[O:38])[CH2:37][CH2:36]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cc(Cl)c(Cl)cc31)CC2
Temperature: 60 °C

Procedure:
A mixture of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 9.2 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one and 90 parts of N,N-dimethylformamide is stirred and heated at 60° C. for one hour. The reaction mixture is evaporated and water is added to the residue. The whole is alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is triturated in 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2 parts of 8-[3-(5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 275.2° C.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Al+3].[Cl-].[Cl-].[Cl-].[Si]([C:30]#[N:31])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>ClCCCl.CCOC(C)=O>[N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:30]#[N:31])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Temperature: 85 °C
Yield: 56.7 %

Procedure:
To a suspension of 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (0.906 g, 3.24 mmol) in 1,2-dichloroethane (48 mL) was added AlCl3 (2.028 g, 15.3 mmol). The reaction was allowed to stir for 10 nm in and then TMSCN (2.04 mL, 15.3 mmol) was added. The reaction was sealed and heated to 85° C. for overnight. The reaction mixture was poured into a separatory funnel containing K2CO3 (aq satd) (200 mL) and EtOAc (200 mL). Extraction with EtOAc (3×200 mL) was performed. The combined organics were dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in DMSO and purified by Gilson preparatory HPLC (w/0.1% TFA). The combined fractions were concentrated down under vacuum to remove the CH3CN. The resulting water layer was basified to pH=12 with 5N NaOH, and then extracted with EtOAc (3×150 mL). The combined fractions were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (0.53 g, 56.7%). EI-MS m/z 289 (M-H)+Rt (1.43 min).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 16.2 %

Procedure:
The title compound (40 mg, 16%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (239 mg, 0.711 mmol, prepared in example 1), 4-methylbenzeneboronic acid (116 mg, 0.853 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), 2 M sodium carbonate (255 mg in 1.2 mL water), and 1,2-dimethoxyethane (4.75 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 207 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified is by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH3:37][NH:38][CH3:39]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]([CH3:39])[CH3:37])=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Reactant: CNC
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 162) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (93 mg, 540%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH:7]([C:15]([OH:17])=[O:16])[CH2:6]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>[OH-].[Na+].O1CCOCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:8]2[C@H:7]([C:15]([OH:17])=[O:16])[CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[O:27])=[CH:21][CH:20]=1
Reactant: COc1cc2c(cc1OC)CC(C(=O)O)NC2
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.3 %

Procedure:
To a solution of (S) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.00 g, 2.44 mmol) in 1N aq. NaOH (10 mL), a solution of 4-chlorophenylisocyanate (563 mg, 3.66 mmol) in dioxane (8 mL) was added. The mixture was stirred at room temperature overnight. More 4-chlorophenylisocyanate (600 mg, 3.91 mmol) in dioxane (5 mL) was added. It was stirred for another day. It was then washed with Et2O (2×). The aqueous layer was separated, acidified with 4N HCl to pH 1 to 2. The product was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo to give a solid (1.50 g), which was sufficiently pure to be used in the next reaction. MS 391.1 and 393.1 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][N:36]([CH3:38])[NH2:37].CCN(C(C)C)C(C)C>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:35][N:36]([CH3:38])[NH:37][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:9]
Reactant: CN(C)N
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NN(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To the acid 3-(methoxycarbonyl)benzoic acid (253 mg, 1.40 mmol) in CH2Cl2 at rt, EDCI (312 mg, 1.64 mmol) and HOBT (189 mg, 1.40 mmol) were added and stirred at rt for 20 min. To that mixture, N,N-dimethyl hydrazine was added followed by DIPEA (404 mg, 14.0 mmol). Reaction mixture was stirred at rt for 16 h. Then reaction mixture was diluted with chloroform, washed with water, brine and dried. Crude residue was purified by column chromatography to yield 60% of methyl 3-(2,2-dimethylhydrazinecarbonyl)benzoate.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:12]=[CH:13][CH:14]=2)C=CC=CC=1.O>[Pd].C(O)C.C(O)(=O)C>[CH2:15]([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCC(O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCc1cccc(O)c1
Yield: 387.5 %

Procedure:
A mixture of 3.0 grams (0.008 mole) of 1-(3-(phenylmethoxy)phenyl]undecanol and 0.5 gram (catalyst) of 10% palladium on charcoal and 50 mL of acetic acid in 50 mL of ethanol was hydrogenated using a Parr hydrogenator. Upon the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered and concentrated under reduced pressure to a residual oil. NMR analysis of the oil indicated that the phenol portion of the molecule was completely unprotected, and the benzylic hydroxyl was about 70% removed. The oil was then mixed with. 16.5 grams (0.047 mole) of 1-[3-(phenylmethoxy)phenyl]undecanol, 2.0 grams of 10% palladium on charcoal, 10 mL of water, and 50 mL of ethanol in 130 mL of acetic acid. The mixture was then hydrogenated as previously described, using the Parr hydrogenator. The reaction mixture was filtered and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 9:1 petroleum ether and diethyl ether and 8:2 petroleum ether and diethyl ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 7.7 grams of 3-undecylphenol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[OH:4][CH2:3][CH:2]([NH:1][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(CO)C(=O)O
Product: Cc1ccc(S(=O)(=O)NC(CO)C(=O)O)cc1

Procedure:
In analogy to example 2, DL-serine was reacted with 4-toluenesulfonyl chloride to give 3-hydroxy-2-(toluene-4-sulfonylamino)-propionic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][C@H:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH2:23][NH2:24])[CH2:16]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[CH:4]2[CH:9]([CH:10]=[CH:11][C:2]([NH:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[N:17]3[CH2:18][CH2:19][NH:20][C@H:15]([CH3:14])[CH2:16]3)=[CH:3]2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: C[C@@H]1CN(c2ccccc2CN)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2ccccc2CNC2=CC3C(Cl)=NNC(=O)C3C=C2)CCN1
Yield: 12.1 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (670 mg, 2.582 mmol), 2-((R)-3-methyl-piperazin-1-yl)-benzylamine (542 mg, 2.693 mmol), Pd2(dba)3 (246 mg, 0.269 mmol), rac-BINAP (505 mg, 0.811 mmol) and NaOtBu (774 mg, 8.054 mmol) in DMA (13 mL) was heated at 80° C. for 2 h. The mixture was allowed to cool, filtered through celite and rinsed with EtOAc (this layer was discarded), then MeOH. The MeOH filtrate was concentrated followed by column chromatography (EtOAc/MeOH+0.1% NH4OH) afforded 4-chloro-6-[2-((R)-3-methyl-piperazin-1-yl)-benzylamino]-4a,8a-dihydro-2H-phthalazin-1-one (121 mg) as a brown solid. 1H (400 MHz, d6-DMSO) δ: 1.22 (d, 3H), 2.73 (m, 1H), 2.95 (m, 1H), 3.1 (m, 5H), 4.47 (d, 2H), 6.67 (s, 1H), 7.06 (m, 1H), 7.14 (d, 2H), 7.25 (m, 1H), 7.35 (d, 1H), 7.78 (t, 1H), 7.90 (d, 1H), 12.33 (s, 1H) ppm; m/z (M+1) 384.28.
Reaction SMILES: CS[CH:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6]C)=[O:5].[OH-].[K+].O.S(=O)(=O)(O)O.[CH3:21]OCCOC>>[CH3:21][CH:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(SC)c1cccs1
Reactant: COCCOC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Methyl α-methylthio(2-thienyl)acetate (1.956 g) was dissolved in 20 ml of 1,2-dimethoxyethane, and 10 ml of a 2N aqueous solution of potassium hydroxide was added. The mixture was stirred at room temperature for 2 hours and 50 minutes. Water (20 ml) and 10 ml of 3N sulfuric acid were added. The mixture was extracted four times with 50 ml of diethyl ether. The ethereal layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1.668 g of α-methyl(2-thienyl)acetic acid as pale yellow crystals. Recrystallization from diethyl ether/n-hexane afforded crystals having a melting point of 75 to 75.5° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.[Cl-].[Na+].O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][N:7]1[C:8]2[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[NH:4][CH2:5][C:6]1=[O:12]
Reactant: COC(=O)CBr
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (150 mg, 0.90 mmol) in DMF (3.0 ml) was added sodium hydride (60%, 36 mg, 0.90 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was cooled again in an ice/water bath and methyl bromoacetate (85 μl, 0.90 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and separated. The organic phase was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 40:60) to give a white solid; yield 140 mg, 65%.