Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C.O.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:37][C:27]1[CH:28]=[CH:29][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 87.5 %

Procedure:
In a 300 mL, 3-necked round bottom flask under N2, 4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylic acid (10 g, 28 mmol, step 4 of Example 8) was placed and a solution of p-toluenesulfonic acid monohydrate (16 g, 84 mmol) in i-propanol (150 mL) was poured at room temperature. The resulting mixture was stirred at 60° C. for 7 h under N2 and triethylamine (8.6 mL, 62 mmol) was added dropwise slowly during the period of 2 hr with seeding. The white precipitate was formed during the addition of triethylamine. The resulting white suspension was stirred at 60° C. for 3 h, at 50° C. for 5 h and at room temperature for 10 h. The suspension was filtered and the obtained solid was washed with i-propanol (100 mL), dried at 50° C. for 5 h to give 10.5 g (87%) of the titled compound as white powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:19][CH:9]2[CH2:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:2][CH3:3]>ClCCCl.C(O)(=O)C.[O-2].[O-2].[Mn+4]>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:19][C:9]2=[CH:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2c(C(N)=O)ccc3c2C(CN3)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCN(CCC)C1Cc2c[nH]c3ccc(C(N)=O)c(c23)C1
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
Manganese dioxide (43.3 g, 498 m moles) was suspended in 1,2-dichloroethane (400 ml) in a 2-liter flask. The manganese dioxide suspension was cooled to -5° C., and acetic acid was added to the flask (300 ml). The manganese dioxide suspension was again cooled to -5° C. 4-(di-n-propyl)amino-6-aminocarbonyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole (100 g, 332 m moles) was dissolved in acetic acid (300 ml). The solution was added to the manganese dioxide suspension while the temperature was maintained between -6° and 0° C. The reaction mixture was stirred for 2.5 hours. Filter aid (45 g) was added to the reaction mixture, which was then filtered. The filter cake was washed with acetic acid (600 ml) and dichloroethane (800 ml). The filtrate was evaporated in vacuo. The residue was taken up in toluene (500 ml), and the solution was evaporated in vacuo. The residue was again taken up in toluene (500 ml), and the solution was evaporated in vacuo. To the residue (186 g) was added aqueous sodium hydroxide (2.0 N, 700 ml). The mixture was stirred for 30 minutes, and filter aid (45 g) was added to the mixture. The mixture was filtered, and the filter cake was washed with 1,2-dichloroethane (500 ml). The organic phase of the filtrate was washed with water (700 ml), washed with saturated sodium chloride (700 ml), and then dried over sodium sulfate. The solvent was evaporated in vacuo to afford 96.8 g of the desired compound which was identified by comparison of nmr spectrum with the known compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[CH3:12][CH2:13][CH2:14][C:15](=O)[CH2:16][CH2:17][CH3:18].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:13]([C:14]1[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:9]=2)[NH:10][C:15]=1[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: COc1ccc(NN)cc1
Reactant: CCCC(=O)CCC
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCCc1[nH]c2ccc(OC)cc2c1CC
Temperature: 10 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A mixture of 4-methoxyphenyl hydrazine hydrochloride (3.0 g), 4-heptanone (1.94 g), and sulfuric acid (1.3 ml) in ethanol (10 ml) was stirred at 10° C. for 3 hours. The cooled mixture was poured into aqueous sodium bicarbonate solution, such that the pH was adjusted to 9. The solution was extracted with ethyl acetate, the organic layer separated, washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude product was chromatographed on silica gel using 25%-ethyl acetate in n-hexanes as eluent to yield 3-ethyl-5-methoxy-2-propylindole (3.22 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:12][C:10]3[O:11][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:8][N:9]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: Sc1nnc(-c2ccncc2)o1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(-c4ccncc4)o3)C(=O)O)cc2)cc1

Procedure:
Example 39 is prepared from 5-(4-pyridinyl)-1,3,4-oxadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5C=CN=CC=5)=[CH:26][C:25]=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C2[N:49]=[C:48]([CH3:50])[O:47][N:46]=2)=CC=1)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:49]=[C:48]([CH3:50])[O:47][N:46]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(-c2noc(C)n2)cc1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Product: Cc1nc(-c2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)no1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 3-(4-ethynyl-phenyl)-5-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]([NH2:26])([CH3:25])[CH3:24]>CS(C)=O.C(Cl)Cl>[C:23]([NH:26][C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:25])([CH3:24])[CH3:22]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)Nc1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Yield: 25 %

Procedure:
A solution of 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (210i, 75 mg, 0.266 mmol) and 2-methylpropan-2-amine (56.1 μl, 0.531 mmol; Aldrich) in DMSO (2.6 ml) was stirred at 100° C. for 1 h. The mixture was diluted with DCM (150 ml), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. The impure material was dissolved in DMSO (˜20 mg/ml) and injected (4×1.0 ml) onto a Shimadzu preparatory LC (rpHPLC: Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA) before the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with DCM, separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(3-(tert-butylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (210, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 9H) 2.87 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 6.95 (br. s., 1H) 7.07 (d, J=2.15 Hz, 1H) 7.34 (t, J=7.82 Hz, 1H) 7.58 (s, 1H) 7.61 (dd, J=7.92, 1.27 Hz, 1H) 7.90 (dd, J=7.53, 1.27 Hz, 1H) 8.38 (s, 1H) 12.13 (br. s., 1H). MS (ESI, pos. ion) m/z: 336.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([C:11]2[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2ncccc2cc1-c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-3-phenyl-1,8-naphthyridine (Rani, H. S.; Mogilaiah, K.; Sreenivasulu, B. Indian J. Chem. Sect. B. 1996, 35, 106; 154 mg, 0.64 mmole), 4-formylphenylboronic acid (144 mg, 0.96 mmole), 2 M Na2CO3 (0.64 mL, 1.28 mmole), and Pd(PPh3)4 (37 mg, 0.03 mmole) were combined in dioxane (3 mL) in a sealed microwave vessel. The mixture was degassed (3× vacuum/N2) then microwave irridiated at 150° C. for 30 min. The mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (60% EtOAc/hexanes) gave the title compound as a yellow foam (10-1): 1H-NMR (500 MHz, CDCl3) δ 10.02 (s, 1 H), 9.19 (dd, J=1.95, 2.20 Hz, 1 H), 8.28 (dd, J=1.95, 6.35 Hz, 1 H), 8.26 (s, 1 H), 7.79 (d, J=8.30 Hz, 2 H), 7.73 (d, J=8.05 Hz, 2 H), 7.57 (m, 1H), 7.35 (m, 2H), 7.27 (m, 3 H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].[I-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O.O1CCCC1>[CH2:28]([O:4][C:3]1[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][CH:10]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOc1cccc(O)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To a suspension of 29.6 g of sodium hydride in 215 ml of N,N-dimethylformamide was added dropwise over 1.5 hours a solution of 54.33 g of resorcinol in 145 ml of N,N-dimethylformamide and 72 ml of tetrahydrofuran. The resulting mixture was cooled to 0° C. and 7.4 g of sodium iodide added followed by the dropwise addition of 155.0 g of hexadecylbromide over 1 hour. The bath was removed and the mixture stirred at ambient temperature for 17 hours. The mixture was diluted with 500 ml of iced dilute hydrochloric acid, extracted with ether and filtered. The ether layer was dried over magnesium sulfate and evaporated to an oil which was purified by chromatography on silica gel using ethyl acetate-hexanes giving 37.2 of the desired compound as a white solid, m.p. 58°-59° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:20]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)CC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(Cc2ccccc2)CC1

Procedure:
Ethyl 4-piperidylacetate was dissolved in 50 ml CH2Cl2 while chilling the mixture on an ice bath, 3.1 ml (22 mmol) triethylamine then benzyl chloride was added; the mixture was refluxed for 2 hours. After cooling the organic layer was extracted with water, brine and then dried over magnesium sulfate. After crystallization, 2.05 g of ethyl N-benzyl-4-piperidylacetate was obtained (Formula XI: Y'=CH2, alkyl=C2H5).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].C1C(=O)N([Br:26])C(=O)C1>CC#N>[Br:26][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccccc2c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A stirred solution of tert-butyl 2-naphthylcarbamate (104) [PCT Int. Appl. (2002) WO 02/067930, Searcey, M., Patterson, L. H.] (20.3 g, 83 mmol) in MeCN (150 mL) was treated portionwise at 0° C. with NBS (17.82 g, 100 mmol), then stirred for a further 2 h at 0° C. The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2. The solution was filtered through a short column of silica gel, and the product was recrystallised from MeOH to give tert-butyl 1-bromo-2-naphthylcarbamate (105) (24.09 g, 90%), as a white solid: mp 90-91° C.; 1H NMR [(CD3)2SO] δ 8.82 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.96 (d, J=9.6 Hz, 1H), 7.93 (d, J=9.3 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.56 (t, J=7.4 Hz, 1H), 1.49 (s, 9H). Anal. (C15H16BrNO2) C, H, N, Br.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]([O:35][CH3:36])([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28]([Cl:34])=[CH:29][CH:30]=3)[N:25]=2)[CH:17]=1)[CH:13]1[CH2:15][CH2:14]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:34][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[CH:33][C:24](/[CH:23]=[CH:22]/[C:18]3[CH:17]=[C:16]([C:12]([O:35][CH3:36])([CH:13]4[CH2:15][CH2:14]4)[CH2:11][O:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:37])=[O:2])[CH:21]=[CH:20][CH:19]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccccc1OCC(OC)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(COc1ccccc1C(=O)O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C1CC1

Procedure:
A stirred solution of ester 45 (1.0 g, 0.0019 mol) in THF (10.0 ml) was treated with a 20% aqueous solution of tetra-n-butylammonium hydroxide (2.5 ml), at ambient temperature for 15 hours. The solvents were evaporated, the resulting mixture was diluted with aqueous acetic acid and extracted with dichloromethane (30 ml) followed by usual workup and FC to give (Ia.96) (0.8 g, 79%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](OCC)=[O:12].[BH4-].[Na+].CC(C)=O>O1CCCC1.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: CCOC(=O)C1CCc2ccccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
A solution of ethyl 2-chromanecarboxylate (1.575 g, 7.68 mmol) in a mixture of tetrahydrofuran (75 ml) and water (2 ml) was added with sodium borohydride (0.686 g, 18.2 mmol) in small portions and the mixture was left under stirring at room temperature for 48 h. Afterwards the mixture was cooled at -10° C. and added with acetone (47 ml) stirring at room temperature for 0.5 h. Subsequently water (100 ml) was added and the mixture was extracted with dichloromethane. The combined organic phases were dried and the solvent was removed by evaporation under reduced pressure, thereby obtaining 1.218 g of the title product (97% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26](O)=[O:27])=[C:19]3[N:18]=2)[CH:9]=[CH:8][CH:7]=1.CN(C=O)C.C(Cl)Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O>[C:17]12[CH:22]=[CH:21][N:20]3[C:19]([N:18]=1)=[C:25]([CH:24]=[N:23]3)[C:26](=[O:27])[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([CH:9]=[CH:8][CH:7]=1)[C@@H:12]1[N:13]2[CH2:14][CH2:15][CH2:16]1
Reactant: NCCCOc1cccc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NCCCOc2cccc(n2)[C@H]2CCCN2c2ccn3ncc1c3n2
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To a solution of (R)-5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (70 mg, 0.18 mmol) in 1:2 DMF/DCM (9 mL) was added EDCI (110 mg, 0.55 mmol) followed by HOBT (74 mg, 0.55 mmol) at ambient temperature. After stirring for 10 minutes, TEA (0.077 mL, 0.55 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was diluted with EtOAc, washed with saturated NH4Cl, saturated NaHCO3, and brine, then dried (MgSO4), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 2% MeOH/DCM to yield the title product (30 mg, 45% yield). MS (apci) m/z=365.2 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1>C(O)C.[Pd]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: CNc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CNc1cccc(N)c1
Temperature: 70 °C
Yield: 96 %

Procedure:
8 g of the precipitate was dissolved in 20 mL of 95% ethanol, 1 g of a catalyst having 5 wt. % Pd on a carbon support was added and hydrogenation of the N-methyl-3-nitroaniline was carried out at 50 psig (337 kPa gage) for about 10 minutes, during which time the temperature increased to about 70° C. The hydrogenated mixture was cooled to room temperature, filtered to recover the solids, which were then washed with methanol and the liquid filtrates combined. Finally, the liquids were concentrated under vacuum and distilled through a short path Kugelrohr oven at about 140° C. and 3 torr to produce a 96% yield of N-methyl m-phenylenediamine.
Reaction SMILES: [Na].[C:2]1([CH3:9])[C:3](C)=[CH:4][CH:5]=[CH:6][CH:7]=1.[P:10]([O-:17])([O:14]CC)[O:11]CC.C1(C(Cl)(Cl)Cl)C=CC=CC=1>O1CCCC1>[C:2]1([C:9]([P:10]([OH:17])(=[O:11])[OH:14])([P:10]([OH:17])(=[O:14])[OH:11])[P:10]([OH:17])(=[O:14])[OH:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: Cc1ccccc1C
Agent: [Na]
Solvent: ClC(Cl)(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=P(O)(O)C(c1ccccc1)(P(=O)(O)O)P(=O)(O)O
Temperature: 100 °C

Procedure:
There were mixed together 23.0 grams (1.0 mole) of sodium metal along with 90 cc. of xylene and 80 cc. of tetrahydrofurane and the mixture placed under a nitrogen atmosphere. There were then added over a 35 minute period 138.10 grams (1.0 mole) of diethyl phosphite using external cooling to control the reaction exotherm and maintain the temperature at 60° to 65° C. After addition was complete the mixture was heated to 100° C. and maintained there for about 1 hour until there was no more sodium. The mixture was cooled to 60° C. and there was started the addition of 64.5 grams (0.33 mole) of benzotrichloride (α,α,α-trichlorotoluene). The exothermic reaction was cooled to maintain the temperature at 60° to 65° C. during the 25 minute addition period. The mixture was heated at 70° to 75° C. for 7 hours and the sodium chloride filtered off. The product in the pot was then subjected to distillation, terminal conditions being a pot temperature of 205° C., distillate temperature 125° C. and pressure 4 mm. The solid residue in the pot was hexaethyl phenyl methane triphosphonate. This product was hydrolyzed and the hydrolysis product purified as in Example 1 to obtain phenyl methane triphosphonic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](Cl)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]5[C@H:32]([CH3:33])[CH2:31][NH:30][CH2:29][C@@H:28]5[CH3:34])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH:35]1(NC(C2C3C=C(C4C(C)=CN=C(Cl)N=4)SC=3C=CC=2)=O)CC1.C(N1C[C@@H](C)N(CCCN)[C@@H](C)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:35])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]5[CH:32]([CH3:33])[CH2:31][NH:30][CH2:29][CH:28]5[CH3:34])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C[C@@H]1CNC[C@H](C)N1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1CCCN
Product: Cc1cnc(NCCCN2C(C)CNCC2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[3-(2,6-cis-dimethylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 3-(4-benzhydryl-2,6-cis-dimethylpiperazin-1-yl)-propylamine as a yellow solid. ES+(m/z) 479 [M+H].
Reaction SMILES: [I-].[OH:2][CH2:3][CH:4]1[CH:9]2[C:10]3[C:15]([CH2:16][CH2:17][N:8]2[CH2:7][O:6][CH:5]1SC)=[CH:14][C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3.C(O)C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[OH:2][CH2:3][CH:4]1[CH:9]2[C:10]3[C:15]([CH2:16][CH2:17][N:8]2[CH:7]([CH:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[NH:27])[O:6][CH2:5]1)=[CH:14][C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=3
Reactant: COc1cc2c(cc1OC)C1C(CO)C(SC)OCN1CC2
Reactant: Nc1ccccc1
Agent: [I-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C1C(CO)COC(C3C=CC=CC3=N)N1CC2
Reaction time: 3 h

Procedure:
To a solution of 4.51 g (0.01 mole) of 1-(hydroxymethyl)-2-(methylthio)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3-a]isoquinoline iodide in ethanol 9.3 g (0.10 mole) of aniline are added, and the reaction mixture is boiled for 3 hours. Upon cooling the product separates from the mixture in crystalline form.
Reaction SMILES: CC1C=CC(S([NH:11][CH:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][P:14](=O)([O:18]CC)[O:15]CC)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br.NC(CC1C=CC=CC=1)CP(=O)(O)O.[NH4+].[OH-].O>O.C(O)(C)C>[NH2:11][CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][PH:14](=[O:15])[OH:18]
Reactant: CCOP(=O)(CC(Cc1ccccc1)NS(=O)(=O)c1ccc(C)cc1)OCC
Agent: Br
Agent: NC(Cc1ccccc1)CP(=O)(O)O
Agent: [NH4+]
Solvent: O
Solvent: Oc1ccccc1
Solvent: CC(C)O
Product: NC(Cc1ccccc1)C[PH](=O)O

Procedure:
A mixture of [2-[[(4-methylphenyl)sulfonyl]amino]-3-phenylpropyl]phosphonic acid, diethyl ester (5.9 g., 13.9 mmole), phenol (8.0 g., 85.1 mmole), and 48% aqueous hydrobromic acid (50 ml.) is refluxed for 5.5 hours. The cooled mixture is diluted with water (50 ml.) and washed with ethyl acetate (2×50 ml.). The aqueous phase is evaporated to dryness, taken up in water (30 ml.) and evaporated again. This is repeated twice more. Finally, the residue is taken up in water and applied to an AG 50 W-X2 (H+ form) column (60 ml. bed volume) and eluted first with water then with 5% pyridine-water. The fractions containing the desired product are combined and evaporated to dryness. The solid residue is triturated with acetonitrile to give 2.55 g. of (2-amino-3-phenylpropyl)phosphonic acid as an off-white crystalline solid; m.p. 347° (dec.); TLC (isopropanol/conc. NH4OH/water; 7:2:1) spot at Rf =0.27.