Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[C:4]([F:25])[CH:3]=1.CN(C)C(C1SC2C(=NC=CC=2OC2C=CC(N[C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[S:48])=CC=2F)C=1)=O>>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[S:48])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:8]2[CH:15]=[C:14]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[S:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: Nc1ccc(Oc2ncnc3sc(C(=O)N4CCCC4)cc23)c(F)c1
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3sc(C(=O)N4CCCC4)cc23)c(F)c1
Yield: 17 %

Procedure:
Starting from the compound 210 and following the procedures described above for the synthesis of compound 8a (scheme 1, step 7, example 1), crude title compound 211 was obtained. It was purified by flash chromatography, eluents DCM and DCM-MeOH-Et3N (97.75:2:0.25) followed by trituration with a mixture of MeOH-EtOAc, to afford title compound 211 in 17% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.43 (s, 1H), 11.80 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.93 (d, 1H, J=11.7/2.3 Hz), 7.53-7.47 (m, 2H), 7.34-7.26 (m, 5H), 3.90 (t, 2H, J=6.7 Hz), 3.83 (s, 2H), 3.55 (t, 2H, J=6.7 Hz), 1.99-1.85 (m, 4H). LRMS (M+1) 536.2 (100%).
Reaction SMILES: C(OCC)(=O)C.C(=O)([O-])O.[K+].[CH:12]#[C:13][CH:14]([OH:17])[CH2:15][CH3:16].[Br:18][C:19](Br)=[N:20][OH:21]>O>[Br:18][C:19]1[CH:12]=[C:13]([CH:14]([OH:17])[CH2:15][CH3:16])[O:21][N:20]=1
Reactant: ON=C(Br)Br
Reactant: C#CC(O)CC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(O)c1cc(Br)no1

Procedure:
Added to 800 ml of ethyl acetate were 8 ml of water, 60.0 g (0.6 mol) of potassium hydrogencarbonate and 73.5 g (0.88 mol) of 1-pentyn-3-ol. Under stirring, 40.5 g (0.2 mol) of dibromoformaldoxime were added at room temperature over 3 hours. After the resultant mixture was stirred at room temperature for 16 hours, water was added and the reaction product was extracted with ethyl acetate. Subsequent to concentration, 3-bromo-5-(1-hydroxypropyl) isoxazole was obtained as oil. It was distilled to collect a fraction at 97°-102° C./2 mmHg.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[N:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][NH2:25])=O)=[N:18][CH:17]=1>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:25][N:24]=[C:22]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][N:18]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC(=O)c1ccncn1
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1nc(-c2ccncn2)n[nH]1

Procedure:
The mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (1.5 g, 6.6 mmol) and pyrimidine-4-carbohydrazide (1.2 g, 8.7 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to yield the desired product as light green viscous oil. LCMS calculated for C14H19N8 (M+H): 299.2; found: 299.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](N)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].C(#N)C.N([O-])=[O:26].[Na+]>OS(O)(=O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([OH:26])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)nc(-c2ccc(Cl)c(OC)c2F)n1
Yield: 60 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (300 mg, 0.97 mmol, see U.S. Pat. No. 7,300,907 B2 for preparation) was slurried in 10 mL 1M H2SO4 plus 3 mL acetonitrile, heated to 75° C. and treated in portions with sodium nitrite (350 mg, 5 mmol) over a period of 10 minutes. After 40 minutes the mixture was cooled and the yellow precipitate was taken up in 40 mL ethyl acetate, washed with 10 mL water, washed with 10 mL brine, dried, and evaporated to give 170 mg (60% yield) 6-hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester; MS m/z 312, 1H NMR (DMSO-d6): δ 7.49 (m, 3H), 3.95 (s, 3H), 3.86 (s, 3H)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[C:16]([O:20][C:21]([NH:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:25]([OH:27])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([NH:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:30][CH:29]=1)[C:25]([OH:27])=[O:26])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 75 °C
Reaction time: 72 h

Procedure:
Potassium carbonate (23.11 g, 140 mmol) and 4-fluorobenzaldehyde (25.0 mL, 233 mmol) were added to a solution of tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (12.5 g, 46.7 mmol) in anhydrous DMF (40 mL). The resulting suspension was refluxed at 75±5° C. under an atmosphere of argon. After 72 hr, the reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with EtOAc (2×150 mL). The aqueous layer was collected, acidified with 5.0 M HCl to pH ˜2.0 and extracted with EtOAc (3×150 mL). The resulting EtOAc layer was extracted with water (2×300 mL) and brine (1×300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired aldehyde 29 as a low melting solid (12.0 g, 69%). 1H NMR (400 MHz, DMSO-d6): 12.9 (br, 1H), 9.93 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.13 (overlapped d, J=8.8 Hz, 2H), 7.13 (overlapped d, J=8.8 Hz, 2H), 5.16 (d, J=8.0 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange solid (324 mg).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 8.2 mg, 0.21 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (45 mg, 0.19 mmol) in THF (1.0 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ˜0.21 mmol) in THF (1.0 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 10 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 36.5 mg (51%) of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][OH:16].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:12][C:11]1([CH2:10][CH2:9][C:7]2[S:8][C:4]([C:1]([CH3:2])=[O:3])=[CH:5][CH:6]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: OCCO
Reactant: CC(=O)CCc1ccc(C(C)=O)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Product: CC(=O)c1ccc(CCC2(C)OCCO2)s1

Procedure:
4-(5-Acetyl-2-thienyl)-2-butanone (Tetrahedron 35, 1979, 329) was reacted with ethylene glycol, triethyl orthoformate and p-toluenesulphonic acid in methylene chloride to give methyl 5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2-thienyl ketone. Oxidation with sodium hypobromite and subsequent hydrolysis gave 5-(3-oxobutyl)-2-thiophene carboxylic acid. With sodium borohydride there was obtained therefrom 5-(3-hydroxybutyl)-2-thiophenecarboxylic acid which was converted in dimethylacetamide with methyl iodide and sodium carbonate into the methyl ester. Treatment with p-toluenesulphochloride in pyridine and reaction with sodium azide in dimethyl sulphoxide gave methyl 5-(3-azidobutyl)-2-thiophenecarboxylate from which there was obtained by saponification the corresponding acid. The acid was treated with thionyl chloride to give the acid chloride from which there was obtained with concentrated ammonia in ether 5-(3-azidobutyl)-2-thiophenecarboxamide. Reduction of the azido group with triphenylphosphine and subsequent hydrolysis gave (R,S)-5-(3-aminobutyl)-2-thiophenecarboxamide of melting point 65°-75°. UV: ε256 =7780; ε275 =9900.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:10][C:11]1[CH:12]=[C:13]([NH2:16])[NH:14][N:15]=1>>[CH3:10][C:11]1[CH:12]=[C:13]2[NH:16][C:3]([CH3:5])=[CH:2][C:1](=[O:7])[N:14]2[N:15]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)CC(C)=O
Product: Cc1cc2[nH]c(C)cc(=O)n2n1

Procedure:
In Step 1, ethyl acetoacetate and 5-methyl-2H-pyrazol-3-ylamine are condensed to form 2,5-dimethyl-4H-pyrazolo[1,5-a]pyrimidine-7-one (1) in refluxing acetic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[N:13][C:12]([NH:16][C:17]1[N:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1)=[CH:11]2.C(N(C(C)C)CC)(C)C>ClCCCl>[C:23]([C:20]1[N:21]=[CH:22][C:17]([NH:16][C:12]2[N:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:1](=[O:3])[CH3:2])=[N:18][CH:19]=1)#[N:24]
Reactant: N#Cc1cnc(Nc2cc3cccc(N)c3cn2)cn1
Reactant: CC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc2cc(Nc3cnc(C#N)cn3)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
Acetyl chloride (13 mg, 0.16 mmol) was added to a solution of 5-(8-aminoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (36 mg, 0.14 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in DCE (1.5 mL). The reaction mixture stirred at room temperature for 16 hours and another portion of acetyl chloride (6.5 mg, 0.08 mmol) was added. Stirring was continued for a further 24 hours. The reaction mixture was washed once with water and the organic phase was dried (Na2SO4) and concentrated to dryness. Preparative HPLC gave N-(3-(5-cyanopyrazin-2-ylamino)isoquinolin-8-yl)acetamide (13.4 mg, 0.044 mmol, 32%). 1H NMR (d6-DMSO, 400 MHz) δ 11.05 (br s, 1H), 10.20 (s, 1H), 9.36 (s, 1H), 8.82 (d, 1H, J=1.2 Hz), 8.72 (d, 1H, J=1.2 Hz), 8.48 (s, 1H), 7.65-7.75 (m, 3H), 2.22 (s, 3H). LC-MS (2) Rt=1.96 min; m/z (ESI+) 305 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:22]3[CH2:23][CH2:24][CH:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:8]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: c1ccc(C2CCNCC2)nc1
Product: Clc1ccc2scc(CN3CCC(c4ccccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene (150 mg 0.9 mmol) and 4-(2-pyridyl)piperidine (181 mg, 1.0 mmol) were processed as described in Example 2 to provide the title compound. 1H NMR (300 MHz, d6-DMSO) δ 2.73 (t, J=1.86 Hz, 4H)) 3.18 (m, 4H) 3.55 (s, 1H) 4.63 (s, 2H) 7.29 (m, 2H) 7.50 (dd, J=8.31, 1.86 Hz, 1H) 7.78 (m, 1H) 8.15 (m, 2H) 8.32 (m, 1H) 8.53 (s, 1H); (ESI) m/z 343 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:12])[CH3:11])[CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:11])[CH3:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1
Reaction time: 16 h

Procedure:
A mixture of (2S,4R)-4-dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Stage B.2, 420 mg), 10% palladium on carbon (80 mg) and MeOH (10 mL) was stirred for 16 h under an atm. of hydrogen. Filtration and evaporation gave the title compound which was used without purification in the following steps.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([C:8]3=O)[CH2:6]1)[CH2:12]2)=[O:4].C([O-])=O.[NH4+:19]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH2:19])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Temperature: 25 °C
Yield: 76.6 %

Procedure:
4-Oxo-adamantane-1-carboxylic acid methyl ester (6.5 g, 31.2 mmol) (prepared following J. Org. Chem. 1983, 48, 1101) was dissolved in MeOH (75 ml). To this solution was added 10% Pd—C (1 g) followed by ammonium formate (10 g, 158 mmol). The reaction mixture was heated under reflux for 1 h after which it was cooled to ambient temperature and filtered through hyflo bed. The clear filtrate was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The aqueous layer was separated, basified with 10% NaOH solution and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulphate and solvent removed under reduced pressure to give 4-aminoadamantane-1-carboxylic acid methyl ester (5 g, 77%). LC-MS (m/z): 210 (M+1). 1H NMR (300 MHz, DMSO-d6): δ 3.6 (s, 3H), 3.2 (d, 1H), 1.4-2.2 (13H, m).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]1([C@H:19]([CH3:25])[C:20](OCC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[O:21]=[C:20]([C@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:25])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)[C@@H](C)c1ccccc1
Reactant: COP(C)(=O)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@@H](C)c1ccccc1)OC
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a stirring solution consisting of dimethyl methylphosphonate (1.392 g, 11.22 mmol) in THF (20 mL) at −78° C. was slowly added n-butyllithium solution (6.6 mL, 11 mmol, 1.6 M solution in hexane). The mixture was stirred for 30 minutes, after which time a mixture consisting of (S)-ethyl 2-phenylpropanoate (1.0 g, 5.6 mmol) in THF (10 mL) was slowly added, and the mixture stirred at −78° C. for two hours before being allowed to rise to room temperature overnight. The reaction mixture was treated with 5% aqueous KHSO4 and extracted with ethyl acetate three times. The combined organic layer was twice washed with a solution of 50:50 water-brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (80:20 v/v) afforded the title compound (1.03 g, 72%) as a colorless oil; TLC Rf 0.4 (solvent system 80:20 v/v ethyl acetate-heptane); MS (ESI+) m/z 257.1 (M+H)+; 1H NMR (CD3OD) δ 7.37-7.22 (m, 5H), 4.01 (q, J=6.71 Hz, 1H), 3.74-3.69 (m, 6H), 3.27-3.2 (m, 1H), 3.09-2.97 (m, 1H), 1.37-1.34 (m, 3H); [α]Tλ=α/cl, [α]21.9D=0.946/(0.01859 g/1.5 mL)(0.5)=+152.6° (c=1.24, CHCl3).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[O:20])=[CH:15][C:14]=1[N+:29]([O-])=O>O1CCCC1>[NH2:29][C:14]1[CH:15]=[C:16]([C:19]([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])=[O:20])[CH:17]=[CH:18][C:13]=1[NH2:12]
Reactant: Nc1ccc(C(=O)C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(=O)C(=O)c2ccccc2)cc1N
Reaction time: 0.33 h

Procedure:
Preparation and polymerization of 3,4-diaminobenzil-A reduction solution made from sodium dithionite (0.6 grams), sodium hydroxide (0.3 grams) and water (10 ml) was stirred under nitrogen. 4-amino-3-nitrobenzil (270 mg) dissolved in tetrahydrofuran (4 ml) was added to the reduction solution. The color changed from pale yellow to dark brown indicating the progress of the reduction. Reaction was completed in 20 minutes and extraction by dichloromethane removed the organic layer. Drying with magnesium sulfate and solvent removal yielded the brown 3,4-diaminobenzil. Upon dissolving the 3,4-diaminobenzil in m-cresol and heating to 180° C. for 3 hours, complete polymerization took place. The polymerization is indicated by bleaching of the reddish brown monomer to a yellowish brown polymer, the polymer may be isolated by precipitation with methanol as yellowish brown powder from the cresol solution.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][NH:23]2>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Reactant: Clc1ncnc2[nH]cnc12
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3[nH]cnc23)C1

Procedure:
EXAMPLE 102 was prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (EXAMPLE 79, Step 3) and 6-chloro-9H-purine:
Reaction SMILES: [CH2:1]([N:3]([C:19]1[N:24]=[N:23][C:22]([C:25](N)=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[OH-:28].[Na+]>C(O)CCC>[CH2:1]([N:3]([C:19]1[N:24]=[N:23][C:22]([C:25]([OH:28])=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1NCc1ccccc1)c1ccc(C(N)=O)nn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCCCO
Product: CCN(Cc1ccccc1NCc1ccccc1)c1ccc(C(=O)O)nn1
Yield: 45 %

Procedure:
6-(N-Ethyl-N-(2-(benzylamino)benzyl)amino)pyridazine-3- carboxamide (0.49 g) in n-butanol was treated with sodium hydroxide pellets (140 mg) and heated at gentle reflux for 9 hours. The reaction was allowed to cool, was evaporated to dryness and the residue taken into water and acidified with acetic acid. The mixture was extracted with ethyl acetate (×2) and the extracts dried and evaporated to give a gum which was purified by MPLC to give the title compound as a brown foam (220 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>C1COCC1>[CH2:1]([O:8][N:9]1[C:10](=[O:28])[C:11]2[C:12](=[CH:13][C:14]([F:18])=[C:15]([F:17])[CH:16]=2)[N:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C:29]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 68.1 %

Procedure:
N-benzyloxy-2-(2,4-difluoroanilino)-4,5-difluoro-benzamide (Example I-4, 5.66 g, 15 mmol) and carbonyldiimidazole (2.83 g, 17 mmol) were combined in 300 mL of THF and heated to reflux for 30 hours. The solution was cooled, concentrated, and redissolved in chloroform. The solution was washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 4.25 g of a solid which was purified by column chromatography (silica gel, CHCl3/MeOH, 98:2) to give 2.0 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[CH2:17]([O:16][C:14]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:2]([NH:1][C:31](=[O:32])[CH2:30][O:29][CH3:28])=[C:3]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[O:15])[CH3:18]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2cc([N+](=O)[O-])ccc21
Product: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(NC(=O)COC)c2cc([N+](=O)[O-])ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)-5-nitroindole (step 1) and methoxyacetyl chloride.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[Br:41][C:42]1[S:46][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:44][CH:43]=1>O1CCCC1.O>[Br:41][C:42]1[S:46][C:45]([S:47]([N:14]2[C:10]([C:9]3[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[C:11]([F:25])[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13]2)(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(Br)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (143 mg) and 5-bromothiophene-2-sulfonyl chloride (196 mg) were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a colorless oil (yield 248 mg, 90%).