Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC1C=CC(N(C)C)=CC=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)(=O)C(C)=C.[CH3:23][N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][OH:31])=[CH:27][CH:26]=1.C(N(CC)CC)C.C1(=O)C=CC(=O)C=C1>C1C=CC=CC=1>[C:1]([O:31][CH2:30][CH2:29][C:28]1[CH:32]=[CH:33][C:25]([N:24]([CH3:23])[CH3:34])=[CH:26][CH:27]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CN(C)c1ccc(CCO)cc1
Reactant: C=C(C)C(=O)OCc1ccc(N(C)C)cc1
Agent: C=C(C)C(=O)Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCc1ccc(N(C)C)cc1

Procedure:
This monomer was synthesized in a manner analogous to the published method used for the synthesis of 4-(dimethylamino)benzyl methacrylate. Thus, 4.55 g (0.0435 mol) methacryloyl chloride in 4.55 g benzene was added dropwise to a solution of 5.0 g (0.03 mol) 4-dimethylaminophenethyl alcohol, 3.64 g (0.036 mol) triethylamine, and 8.7 g benzene in the presence of p-benzoquinone and CuCl(I) with stirring and cooling, keeping the temperature below 15° C. The reaction mixture was left to stir for one hour in a room temperature water bath (about 25° C.). The solution was filtered to remove triethylamine hydrochloride. The benzene filtrate was washed with water and then with saturated sodium carbonate solution, dried over sodium sulfate anhydrous, filtered, and the benzene removed with the rotary evaporator (water bath 20-25° C.). The monomer was distilled in vacuo in the presence of CuCl(I) and 2,2-diphenyl-1-picrylhydrazyl (DPPH), bp=115-122° C./95-100, μHg. The monomer was recrystallized from petroleum ether, mp=42-43° C. The analysis for nitrogen showed 5.86% N (calc. 6.00). NMR δ(ppm): 1.9 (s, 3, CH2═C(CH3)—); 2.8 (m, 2, —CH2—CH2—C6H4—); 2.9 (s, 6, CH3)2); 4.2-4.3 (m, 2, —(O)C—O—CCH2—CH2—); 5.5, 6.1 (d, s, 2, CH2═C); 6.7, 7.1 (d, d, 4, aromitic H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:7](C(O)=O)[CH2:6]2.[C:25]([C:31]([O:33][CH3:34])=[O:32])#[C:26][C:27]([O:29][CH3:30])=[O:28]>C(OC(=O)C)(=O)C>[CH3:30][O:29][C:27]([C:26]1[C:25]([C:31]([O:33][CH3:34])=[O:32])=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:8]2[C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:6][C:7]=12)=[O:28]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1ccc(C(=O)N2c3ccc(OC)cc3CC2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)cc2)n2c1Cc1cc(OC)ccc1-2
Temperature: 120 °C

Procedure:
A mixture of 5-methoxy-1-(4′-methoxybenzoyl)-2,3-dihydro-1H-indole-2-carboxylic acid (4.24 g, 12.9 mmol) and dimethyl acetylenedicarboxylate (2.4 mL, 19.5 mmol) in acetic anhydride (24 mL) was heated for 4.5 hours at 120° C. until no gas eliminated. The dark solution was concentrated in vacuo to dryness and the solid residue was recrystallized from methanol to yield 6-methoxy-3-(4-methoxy-phenyl)-8H-3a-azacyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester, 3.75 g (71%): mp 240-242° C.; 1H NMR (DMSO-d6) δ 3.60 (3H, s, COOMe), 3.73 and 3.77 (each 3H, s, 2×OMe), 3.85 (3H, s, COOMe), 4.09 (2H, s, CH2), 6.55 (1H, d, J=8.8 Hz, ArH), 6.77 (1H, dd, J=2.6 Hz and J=8.8 Hz, ArH), 7.08 (2H, d, J=8.7 Hz, 2×ArH), 7.19 (1H, d, J=2.4 Hz, ArH), 7.42 (2H, d, J=8.7 Hz, 2×ArH). Anal. Calcd. for C23H21NO5: C, 67.84; H, 5.20; N, 3.44. Found: C, 67.83; H, 5.19; N, 3.39.
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:28][CH2:27][C:26]([C:37](O)=[O:38])=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:45][N:46]([CH2:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>ClCCl.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:28][CH2:27][C:26]([C:37]([NH:58][C:57]4[CH:56]=[CH:55][C:54]([CH2:53][N:46]([CH3:45])[CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:60][CH:59]=4)=[O:38])=[CH:25][C:24]=3[CH:40]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccn2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccn2)cc1
Reaction time: 1 h
Yield: 43.4 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-pyridylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (50 mg) in dichloromethane (5 ml). Then, thionyl chloride (17 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this solution was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (31 mg) and triethylamine (287 mg) in dichloromethane (15 ml) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3) to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-pyridylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 73) (31 mg) as yellow amorphous.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][NH2:4].[N+:6]([O-:9])([OH:8])=[O:7].C(OC(=O)C)(=O)C>>[N+:6]([O-:9])([OH:8])=[O:7].[N+:6]([O:5][C@@H:2]([CH3:1])[CH2:3][NH2:4])([O-:8])=[O:7]
Reactant: C[C@H](O)CN
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: C[C@@H](CN)O[N+](=O)[O-]

Procedure:
The procedure described for Example 10a was used with S-(+)-1-amino-2-propanol (960 mg, 12.8 mmol), fuming nitric acid (0.62 mL) and acetic anhydride (9.7 ml) and 2.7 mL fuming nitric acid (2.7 ml) to give the title compound as a light green solid in quantitative yield. 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 3H), 5.32 (m, 1H), 3.24-3.06 (m, 2H), 1.34 (d, J=6.4 Hz, 3H). 13C NMR (CDCl3, 75.45 MHz) δ 78.1, 40.8, 15.9. LRMS (APlMS) m/z 121 (M−HNO3 +H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([CH:34]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH2:36]([OH:39])[C:37]#[CH:38]>[Pd](Cl)Cl.C(NCC)C>[OH:39][CH2:36][C:37]#[C:38][C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:34][C:25]=1[C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1I
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.17 g (1.0 mmole) of palladium chloride, 0.5 g (2.0 mmole) of triphenylphosphine, 0.1 g (0.5 mmole) of cuprous iodide, 15 g (43 mmole) of 5-chloro-2-iodobenzophenone and 60 ml of diethylamine was stirred at room temperature for 20 min. In one portion 6.0 g (107 mmole) of propargyl alcohol was added, and the resulting mixture was stirred for 24 hr. The solvent was removed at reduced pressure and the residue was dissolved in ether. The ether solution was washed with water, dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give the product as a red oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[H][H].[CH3:9][CH:10]([OH:25])[CH:11]([OH:24])[C:12]1[N:17]=[C:16]2[C:18]([N:20]=[C:21]([NH2:23])[NH:22][C:15]2=[N:14][CH:13]=1)=[O:19].S(=O)(=O)(O)O>[Pt]>[CH3:9][CH:10]([OH:25])[CH:11]([OH:24])[CH:12]1[NH:17][C:16]2[C:18]([N:20]=[C:21]([NH2:23])[NH:22][C:15]=2[NH:14][CH2:13]1)=[O:19]
Reactant: CC(O)C(O)c1cnc2[nH]c(N)nc(=O)c2n1
Reactant: [H][H]
Agent: [Pt]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1

Procedure:
Ten milligrams of platinum black was dispersed into 10 ml of 10% aqueous solution of potassium carbonate, and then the catalyst was activated with hydrogen gas. Then, 10 ml of 10% aqueous solution of potassium carbonate containing 50 mg of biopterin was added to the above dispersion. After the catalytic reduction was conducted by agitating the resulting mixture for 20 hours under normal temperature and normal pressure in a hydrogen atmosphere, the reaction mixture was adjusted to pH 1 by adding 20 ml of 10% aqueous solution of sulfuric acid. The catalyst was filtered off from the reaction mixture to give a solution of tetrahydrobiopterin having a (6R)/(6S) ratio of 90/10 as measured by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:14]([OH:15])[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:16][CH3:17])[CH2:12][S:11](=[O:23])(=[O:22])[C:10]3[CH:24]=[CH:25][C:26]([N:28]([CH3:30])[CH3:29])=[CH:27][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:31](O)(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C1(N=C=NC2CCCCC2)CCCCC1.N1(O)C2C=CC=CC=2N=N1>O1CCCC1>[CH2:18]([C:13]1([CH2:16][CH3:17])[CH2:12][S:11](=[O:22])(=[O:23])[C:10]2[CH:24]=[CH:25][C:26]([N:28]([CH3:29])[CH3:30])=[CH:27][C:9]=2[CH:8]([C:4]2[CH:3]=[C:2]([NH:1][C:31]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:39])[CH:7]=[CH:6][CH:5]=2)[CH:14]1[OH:15])[CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(N)c2)C1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)CCCCC(=O)O)c2)C1O

Procedure:
2 g of 5-(3-aminophenyl)-3-butyl-7-dimethylamino-3-ethyl-1,1-dioxo-2,3,4,5-tetra-hydro-1H-benzo[b]thiepin-4-ol, 3.4 g of hexanedioic acid, 1.04 g of dicyclohexylcarbodiimide and 640 mg of benzotriazol-1-ol in 80 ml of tetrahydrofuran are stirred at room temperature overnight. The mixture is concentrated, the residue is taken up in ethyl acetate, excess urea is removed by filtration and the mixture is washed with water. The residue of the dried organic phase is purified by column filtration (SiO2, dichloromethane/methanol=20:1). This gives the product of molecular weight 558.7 (C30H42N2O6S); MS (ESI+): 559 (M+H+).
Reaction SMILES: O[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Br:13]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:13][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC1COc2ccccc2O1
Solvent: CC#N
Product: BrCC1COc2ccccc2O1
Reaction time: 0.5 h

Procedure:
2-Hydroxymethyl-1,4-benzodioxane (17.9 g, 107 mmol) is taken up in acetonitrile (200 mL) and treated with dibromotriphenylphosphorane (50 g, 119 mmol). The mixture is stirred for 30 minutes and evaporated. The residue is taken up in a 1:1 mixture of ether/hexane, and triphenylphosphine oxide is removed by filtration. The solvent is removed by evaporation to give 2-bromomethyl-1,4-benzodioxane as a brownish solid. This material is used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[OH:37].B(O)O>O1CCOCC1.CC(N(C)C)=O>[CH3:36][O:35][C:31]1[CH:32]=[C:33]([C:6]2[N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:8]=3)[CH:4]=[N:3][CH:2]=2)[CH:34]=[C:29]([O:28][CH3:27])[C:30]=1[OH:37]
Reactant: COc1cccc(OC)c1O
Reactant: Brc1cn(-c2ccnc(N3CCOCC3)n2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc(-c2cncn2-c2ccnc(N3CCOCC3)n2)cc(OC)c1O
Temperature: 170 °C
Yield: 96.3 %

Procedure:
To a solution of 4-[4-(4-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine (0.20 g, 0.65 mmol) in anhydrous dioxane (6 ml) and anhydrous DMA (0.6 m) was added tripotassium phosphate (0.28 g, 1.3 mmol) and 2,6-dimethoxy-phenol-boronic acid (0.18 g, 0.91 mmol). The resultant mixture was degassed with sonication for 10 minutes before the addition of bis(tri-butylphospine)palladium (0.017 g, 0.033 mmol) and degassing for a further 5 minutes. The reaction vessel was sealed and heated under the influence of microwave radiation (170° C., 11 min, low absorption setting). Upon completion, the reaction was filtered through a thin silica plug which was then washed with 10% methanol/CH2Cl2. The filtrate was concentrated in vacuo and the crude residue purified by flash chromatography (SiO2) (1:1—EtOAc:Hexanes) to give the desired product (0.24 g, 96%) as a white crystalline solid in analytically pure form. m/z (LC-MSW, ESP):384.4 [M+H]+, R/T=2.90 mins.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=2[S:6][CH:5]=1)=[CH2:3]>[Pd].CCO>[CH3:3][CH:2]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:8][C:7]=2[S:6][CH:5]=1)[CH3:1]
Reactant: C=C(C)c1csc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1csc2c1OCCN(C(=O)OC(C)(C)C)C2
Reaction time: 12 h
Yield: 99.3 %

Procedure:
A mixture of tert-butyl 8-(1-methylethenyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (270 mg), 10% palladium on carbon (50 mg) and EtOH (5 mL) was stirred for 12 hr under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (270 mg, 99.6%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][CH:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:39][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 74.7 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.27 g, 1.26 mmol) were used to afford 0.52 g of the required product. 1H NMR (DMSO-d6): δ 1.31 (4H, m), 1.45 (9H, s), 1.80 (4H, m), 3.22 (1H, m), 3.68 (1H, m), 6.78 (1H, d, J=7.8 Hz), 7.24 (2H, d, J=9.6 Hz), 7.51 (2H, d, J=2.1 Hz), 7.89 (2H, d, J=8.7 Hz), 8.35 (1H, d, J=7.5 Hz).
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[N:10]1.[F:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30](O)=[O:31])[C:23]2=[O:36])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30]([NH:15][CH2:14][C:12]3[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=3)=[O:31])[C:23]2=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cn1cc(CN)cn1
Agent: NCc1cocn1
Product: Cn1cc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)cn1
Yield: 23 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1-methyl-1H-pyrazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 23% yield: mp 165-166° C.; 1HNMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.44-7.37 (m, 3H), 7.27-7.22 (m, 2H), 7.04-6.98 (m, 2H), 6.70 (br s, 1H), 4.45-4.41 (m, 4H), 4.03 (t, J=8.1 Hz, 2H), 3.84 (s, 3H), 3.36 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.5, 164.0, 160.7, 157.0, 152.9, 148.2, 143.0, 138.9, 132.1, 132.0, 129.9, 129.8, 116.0, 115.9, 115.6, 109.0, 47.2, 41.3, 41.0, 39.0, 34.5; MS (ES+) m/z 408.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cccc(O)c2)CC[C@]12CCNC2=O
Reactant: Fc1ccccc1CBr
Product: CC(C)(C)OC(=O)N1[C@@H](c2cccc(OCc3ccccc3F)c2)CC[C@]12CCNC2=O
Yield: 78 %

Procedure:
The title compound (0.420 g, 78%) was prepared from 1,1-dimethylethyl (2R,5R)-2-(3-hydroxyphenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D45, 410 mg, 1.23 mmol) and 2-fluorobenzyl bromide using a similar procedure to that set out earlier in Description 11.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=O)[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.Cl.Cl.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49]1[S:50][C:51]([CH2:54][N:55]2[CH2:60][CH2:59][CH:58]([CH2:61][NH2:62])[CH2:57][CH2:56]2)=[CH:52][N:53]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([NH:62][CH2:61][CH:58]2[CH2:59][CH2:60][N:55]([CH2:54][C:51]3[S:50][C:49]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=4)=[N:53][CH:52]=3)[CH2:56][CH2:57]2)=[O:12])[CH:3]=1
Reactant: Nc1cc(C(=O)O)nc(Cl)c1Cl
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
The compound prepared in Example 406 (0.533 g), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (2.0098 g), the compound prepared in Example 214 (1.3315 g) and triethyl amine were suspended in dimethyl formamide (40 mL) and stirred at room temperature overnight. The reaction mixture was poured onto saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried over with magnesium sulfate and concentrated under reduced pressure to afford the crude material. The crude material was purified by flash column chromatography (eluant gradient elution 1-5% (9:1=methanol:ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.902 g), possessing the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32])[C:6]([C@@H:12]([N:14]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:13])=[N:7]2.NN>O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32])[C:6]([C@@H:12]([NH2:14])[CH3:13])=[N:7]2
Reactant: C[C@@H](c1nc2cccc(Cl)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: C[C@H](N)c1nc2cccc(Cl)c2nc1-c1ccccc1S(C)(=O)=O
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A 5 L three-neck round bottom flask equipped with an overhead stirrer, thermocouple and reflux condenser with a nitrogen inlet was charged with (S)-2-(1-(5-chloro-3-(2-(methylsulfonyl)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione (193 g, 392 mmol), water (1351 mL) and hydrazine, 35 wt. % solution in water (711 mL, 785 mmol). The resulting white slurry was vigorously stirred at 65° C. under nitrogen for 6 h and then it was allowed to cool to rt overnight. After this time LC-MS analysis showed complete conversion to the desired product. The white solid was isolated by filtration, washed with water and dried on the glass filter under a stream of nitrogen for 4 h to give (S)-1-(5-chloro-3-(2-(methylsulfonyl)phenyl)quinoxalin-2-yl)ethanamine (129.7 g). Mass Spectrum (ESI) m/z=362.0 (M+1).
Reaction SMILES: C(OC([N:11]1[CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C:13]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[N:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:13]1[CH2:14][CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)C1CC(c2cccs2)=NN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC(c2cccs2)=NN1

Procedure:
A solution of 5.0 g of (±)-4,5-dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid, t-butyl ester in 75 ml of ethanol containing 0.5 g of 5% palladium on carbon is hydrogenated at atmospheric pressure until the uptake of hydrogen ceases. The catalyst is removed by filtration through Celite and the filtrate is concentrated in vacuo to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10]
Reactant: N#CCc1ccccc1Br
Solvent: C1CCOC1
Product: NCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed 2-(2-bromophenyl)acetonitrile (9.8 g, 49.99 mmol, 1.00 equiv), tetrahydrofuran (50 mL). This was followed by the addition of BH3 solution (250 mL, 1N in tetrahydrofuran) dropwise with stiffing at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The pH value of the aqueous solution was adjusted to 2 with aq. hydrogen chloride (5 N). The aqueous solution was washed with 3×20 mL of EA and adjusted to pH to 11 with sodium hydroxide. The resulting aqueous solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 5 g (50%) of 2-(2-bromophenyl)ethanamine as brown oil.
Reaction SMILES: [I:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:32])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:4].O>C(O)(C)(C)C>[I:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:32])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:4]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Reaction time: 1.25 h
Yield: 68.9 %

Procedure:
A solution of 11β-iodoacetoxy-3α-methanesulphonyloxy-5α-pregnan-20-one (22.2 g) in t-butanol (950 ml) containing water (500 ml) was treated with powdered silica gel (44 g) and refluxed with stirring for 75 minutes. The cooled mixture was filtered and the filtrate was evaporated to small bulk and diluted with water. The precipitated solid was collected by filtration and recrystallized from aqueous methanol to afford title compound (12.77 g). A sample recrystallized from acetone-petroleum ether had m.p. 127°-129°, [α]D +100.5°.