Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C@@H]2COC=N2)C=CC=CC=1.[C:12]([O:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][CH2:27]2)=[CH:23][CH:22]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+](=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N-]>ClCCl>[C:12]([O:20][C:21]1[CH:22]=[CH:23][C:24]2[C@@H:25]3[C@@H:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:26]3[CH2:27][C:28]=2[CH:29]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Oc1ccc2c(c1)CC=C2)c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: C1=N[C@H](c2ccccc2)CO1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H]2Cc3cc(OC(=O)c4ccccc4)ccc3[C@@H]21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(+)-2,2′-Isopropylidenebis[(4R)-4-phenyl-2-oxazoline (849 mg, 2.542 mmol) was added to a stirring solution of 1H-inden-6-yl benzoate from Step D (30 g, 127.119 mmol) and Cu(I) triflate (657 mg, 1.271 mmol) in dichloromethane (300 mL) at rt under nitrogen. The solution was stirred at rt for 4 h. A solution of ethyl diazoacetate (29 g, 254.237 mmol) in dichloromethane (100 mL) was added at it through a syringe pump over a period of 72 h. Solvent was removed under reduce pressure, and the residue was purified by column chromatography on silica gel (PE) to give the title compound (about 50% enantiomeric excess). 1H-NMR (400 MHz, CDCl3): δ 8.18 (d, J=7.1 Hz, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.51 (t, J=7.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 6.96-7.02 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.29-3.35 (m, 1H), 2.95-3.10 (m, 2H), 2.46-2.50 (m, 1H), 1.26-1.33 (m, 4H) ppm. MS: m/z 323.2 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[NH:15][C:14]=12)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Yield: 21.5 %

Procedure:
A mixture of ethyl 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Reference Example 3) (500 mg, 1.30 mmol), 2 M sodium hydroxide solution (6 mL), tetrahydrofuran (3 mL) and ethanol (3 mL) was refluxed for 2 h. The mixture was neutralized by addition of 1 M hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was crystallized from ethyl acetate to give 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100 mg, 22%) as pale brown amorphous solid. Additional material (348 mg, 75%; 97% overall yield) was obtained from the mother liquid: Rf 0.01 (silica gel, ethyl acetate); mp 114-120° C.; 1H NMR (300 MHz, DMSO-d6) δ4.82 (4H, br s), 7.18-7.35 (12H, m), 7.68 (1H, d, J=6.0 Hz); ESI MS m/z 358 [C22H19N3O2+H]+; HPLC (Method A) 98.8% (AUC), tR=17.7 min.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:4][C:5]1[N:6]=[C:7]([N:2]([CH3:3])[CH3:1])[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2cscc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1nc(Cl)nc2cscc12
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.13 g) in ethanol (5 mL) were added 2,4-dichlorothieno[3,4-d]pyrimidine (0.20 g) and triethylamine (0.10 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.156 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.068 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.27 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylaminothieno[3,4-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.037 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C:14](=[O:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br.CCOCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C:14]([OH:18])([CH3:27])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Yield: 56 %

Procedure:
To a solution of benzyl-(3R,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-oxopiperidine-1-carboxylate (1.61 g, 4.44 mmol) in THF (30 mL) at −78° C. a solution of methylmagnesium bromide in ether (3.0 M, 4.4 mL, 13 mmol) was added. The reaction was then quenched by adding aq. NH4Cl, and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20-80% EtOAc in hexanes to give a mixture of the two diastereoisomers of the sub-title compound as a colorless oil (0.95 g, 56%). LCMS calc. for C20H30N2NaO5 (M+Na)+ m/z=401.2. found 401.0.40% of unreacted starting material was also isolated.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)S(OC1C2C(=CC=C(C(OCC[Si](C)(C)C)=O)C=2)C=NC=1)(=O)=O.C(N(CC)CC)C.[CH3:61][N:62]([CH3:66])[C:63](Cl)=[O:64]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:61][N:62]([CH3:66])[C:63]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:64]
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(-c3ccc(O)cc3)c2c1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1ccc(-c2cncc3ccc(C(=O)OCC[Si](C)(C)C)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Into dichloromethane (6.5 mL), 2-(trimethylsilyl)ethyl 4-(4-hydroxyphenyl)isoquinoline-6-carboxylate (234 mg, 0.64 mmol) synthesized from 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate by the same method as in Example 8 (8a) was dissolved, to which triethylamine (178 μL, 1.28 mmol), 4-dimethylaminopyridine (23 mg, 0.19 mmol) and N,N-dimethylcarbamoyl chloride (88 μL, 0.96 mmol) were added, followed by stirring at room temperature for three hours. The resulting reaction liquid was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (260 mg, yield 93%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.BrBr.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(F)ccc2c1
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2cc(CBr)ccc2c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 2-fluoro-6-methylnaphthalene (0.750 g, 4.68 mmol) in carbon tetrachloride (20 mL) was added NBS (0.917 g, 5.15 mmol) and bromine (0.265 mL, 5.15 mmol) followed by AIBN (0.077 g, 0.47 mmol). The reaction mixture was heated to 70° C. and allowed to stir for 4 hours. It was then cooled to room temperature, partitioned between water and EtOAc, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and subjected to silica gel chromatography eluting with 5-50% EtOAc in hexanes to yield 2-(bromomethyl)-6-fluoronaphthalene.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH2:9]([O:16][CH2:17][C:18](Cl)=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:18](=[O:19])[CH2:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)COCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In 50 ml of methylene chloride was added 15.0 g (35.8 mmol)of glycine ethyl ester hydrochloric acid, followed by addition of 9.2 g (75.3 mmol)of 4-dimethylaminopyridine under ice-cooling. After stirring for 10 minutes, 6.5 ml (39.4 mmol)of benzyloxyacetylchloride was added dropwise under ice-cooling over 30 minutes. The temperature was raised up to room temperature, and the mixture was stirred for 12 hours. To the mixture, 20 ml of methylene chloride was added, and filtered. To the filtrate, 5% hydrochloric acid was added, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and 9.0 g of N-benzyloxyacetylglycine ethyl ester was obtained (yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.CO[Si](C)(C)C.F[C:20](=[O:35])[C@H:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]1[CH:26]=[CH:25][S:24][CH:23]=1.CCOC(C)=O>CN(C=O)C>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:20](=[O:35])[C@H:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2c(O)nccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Agent: CO[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2c(O)nccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 6-aminoisoquinolin-1-ol in DMF was added methoxytrimethylsilane and (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate and the solution was stirred at room temperature for 6 h. The mixture was poured into EtOAc, washed with NH4Cl (sat)/HCl (1N) followed by NaHCO3 (0.05%), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH, CH2Cl2) gave pure (R)-tert-butyl 2-(1-hydroxyisoquinolin-6-ylamino)-2-oxo-1-(thiophen-3-yl)ethylcarbamate) (91.8% ee by Chiracel OD-RH).
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CC(N(C)C)=O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CSc1nc2cc([N+](=O)[O-])ccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc([N+](=O)[O-])ccc3o2)CC1
Temperature: 140 °C
Yield: 23.8 %

Procedure:
A mixture of 2-methylsulfanyl-5-nitro-benzooxazole (10.0 g, 47.57 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (14.29 g, 71.36 mmol, 1.5 equiv) in anhydrous DMAc (50 mL) was heated to 140° C. for 72 h. The solution was concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/cyclohexane (1:1) to give 4.1 g (24%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 9H), 1.50-1.53 (m, 2H), 2.11-2.20 (m, 2H), 2.87-3.05 (m, 2H), 3.89-4.01 (m, 1H), 4.05-4.16 (m, 2H), 5.51 (d, J=7.5 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 8.02 (dd, J=8.7 Hz, J=2.3 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 28.40, 32.29, 42.46, 50.88, 79.81, 108.36, 111.99, 116.77, 143.90, 145.23, 152.38, 154.66, 162.69. MS (ISP): 363.5 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].[OH-].[K+]>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Cc1cccc(O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 155 °C

Procedure:
To a mixture of 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 6.7 parts of 2,3-xylenol 0.2 part of potassium hydroxide was added, and the mixture was heated at 155° C. for 20 hours. The reaction mixture was cooled and then dissolved in 100 parts of ether. The solution was washed three times with 50 parts of 2 N-sodium hydroxide aqueous solution and extracted three times with 2 N-hydrochloric acid aqueous solution. The extract was washed with 50 parts of ether and was made alkaline by adding 2 N-sodium hydroxide solution gradually thereto. Then, the ether extraction was conducted three times and the extract was condensed and allowed to stand in a cool place. As a result, crystals were formed which were recrystallized twice from ether to yield 8.3 parts of 1-(2', 3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C. Results of infra-red spectrum analysis and ultraviolet ray absorption analysis of the product are as follows:
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2ncccc2C)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
Diethyl 3-(3-methylpyridin-2-yloxy)benzylphosphonate (4.3 g, 13 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.05 mL, 0.28 mmol) were combined in THF (150 mL). Sodium hydride (564 mg, 60% dispersion in mineral oil, 14.1 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.81 g, 14.1 mmol) in THF (15 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30%, EtOAc:heptane) to afford the title compound (3.9 g, 80% yield) as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15]C(=O)[O-])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])NCC1CCN(c2ccnc(Cl)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of (1-(2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate (Example 11, step i, 2.32 g, 6.73 mmol) in CH2Cl2 (30 ml) was added trifluoroacetic acid (6.0 ml, 81 mmol). After stirring for 3 h at room temperature the solvents were removed under reduced pressure to give (1-(2-chloropyrimidin-4-yl)piperidin-4-yl)methanamine 2,2,2-trifluoroacetate as a white solid (1.71 g). The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([O:21]C(C)C)([O:17]C(C)C)=[O:16])=[C:4]([NH2:25])[N:3]=1.Br[Si](C)(C)C>ClCCl.CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]/[CH:13]=[CH:14]/[P:15]([OH:21])([OH:17])=[O:16])=[C:4]([NH2:25])[N:3]=1
Reactant: CC(C)OP(=O)(/C=C/CCn1cnc2c(N)nc(N)nc21)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(N)c2ncn(CC/C=C/P(=O)(O)O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a solution of (E)-2,6-diamino-9-[4-(diisopropoxy-phosphoryl)but-3-enyl]purine (144mg, 391 μmol) in dichloromethane (10 ml) was added bromotrimethylsilane (1.20 g, 7.82 mmol) and the mixture stirred at room temperature under dry nitrogen for 18 hr. The resulting white suspension was evaporated to dryness and the residue azeotroped with methanol (×6). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give a product which n.m.r. analysis showed to be the monoester. To a suspension of the monoester (approx. 306 μmol) in dry N,N-dimethylformamide (10 ml) was added bromotrimethylsilane (1.16 g, 7.58 mmol) and the resulting solution was stirred at room temperature under dry nitrogen for 18 hr. The solution was evaporated to dryness and the residue azeotroped with methanol (×3) then acetone-water (1:1) (×3). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give (E)-2,6-diamino-9-(4-phosphonobut-3 -enyl)purine as a white solid (30 mg, 27%), m.p. >325° C.; λmax (MeOH) 256 (6,570) and 285 (6,490)nm; υmax (KBr) 3410, 1710, 1670, 1630, 1590, 1420, 1220 and 135 cm-1 ; δH [(CD3)2SO+one drop NH4OH solution] 2.50 (2H, m, CH2) 4.05 (2H, t, J 7 Hz, CH2N), 5.70 (1H, pseudo-t, J 17 Hz, PCH=CH), 5.81 (2H, s, NH2), 6.10 (1H, pseudo-tt, J 7 Hz and 20 Hz, PCH=CH), 6.69 (2H, s, NH2) , 7.76 (1H, s, H-8); FABMS thioglycerol) 285 (MH+).
Reaction SMILES: [C:1]1([CH2:11][CH2:12]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1>CN(C)P(N(C)C)(N(C)C)=O>[C:1]1([CH2:11][CH2:12][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCc1cccc2ccccc12
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCc2cccc3ccccc23)cc1
Temperature: 110 °C

Procedure:
A solution of 4.7 g. of 2-(α-naphthyl)ethyl bromide and 6.6 g. of ethyl p-aminobenzoate in 50 ml. of hexamethylphosphoramide is stirred and heated at 110° C. for 16 hours. The mixture is cooled, diluted with 50 ml. of water and filtered to give a crude product, which is recrystallized from ethanol. Recrystallization gives ethyl 4-[2-(α-naphthyl)ethylamino]benzoate as white crystals, m.p. 104°-106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48](Cl)=[O:49])[N:47]=1>C(Cl)Cl>[CH3:42][C:43]1[S:44][CH:45]=[C:46]([C:48]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[O:49])[N:47]=1
Reactant: Nc1cc(-c2cncc(NS(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}benzenesulfonamide (100 mg) was dissolved in DCM (5 ml) and pyridine (0.024 ml) was added. The reaction was stirred at RT for 2 min before 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added. The reaction was stirred at RT for 18 h. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (10 mg) was added and stirring continued for 2 h at RT. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (35 mg) was added and the reaction stirred at RT for 18 h before being quenched with water. DCM was added and the reaction was passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:MeOH (1:1, v/v, 1 ml) and purified by MDAP (method E). The desired dried intermediate was dissolved in MeOH and 2M NaOH (1 ml) was added. The reaction was stirred at RT for 30 min. The reaction was neutralised with 2M HCl (aq) then evaporated to dryness. The residue was dissolved in MeOH and loaded onto a SCX-2 SPE cartridge pre-conditioned with MeOH. After eluting with MeOH then 10% NH3 in MeOH, the basic fraction was evaporated to dryness to give the title compound (22 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[C:14]3([CH3:22])[N:18]([CH2:19][CH2:20][C:8]2=1)[C:17](=[O:21])[CH2:16][CH2:15]3.[CH3:23]I>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:23])[C:9]1[C:14]3([CH3:22])[N:18]([CH2:19][CH2:20][C:8]2=1)[C:17](=[O:21])[CH2:16][CH2:15]3
Reactant: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)CCC31C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2C)C2(C)CCC(=O)N2CC1

Procedure:
Sodium hydride (1.06 g. of about a 50% dispersion in mineral oil) is stirred under nitrogen with 5.41 g. 1,2,5,6,11,11b-hexahydro-8-methoxy-11b-methyl-3H-indolizino[8,7-b]indol-3-one [S. Wawzonek and J. D. Nordstrom, J. Med. Chem., 8, 265 (1965)] in 100 ml. dry dimethylformamide for one-half hour. The brown solution is cooled in an ice-water bath as 3.41 g. methyl iodide (1.50 ml.) is added. After one-half hour of cooling, the reaction mass is allowed to stand at about 25°C. for sixteen hours. The dimethylformamide is removed in vacuo and the residue is twice triturated with 50 ml. hexane, dissolved in chloroform and washed with water. After drying (sodium sulfate), the solvent is removed and the solid is twice recrystallized from ethyl acetate, thus affording 4.30 g. of the title compound, m.p. 164°-7°C.; λmaxCHCl3 6.02, 6.19 μ; NMR (CDCl3); δ 1.60 (singlet, 11b-methyl), 3.68 (singlet, 11-methyl), 3.83 (singlet, methoxyl) ppm.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13]>C(OCC)(=O)C>[CH2:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH2:7][S:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13]
Reactant: CCSCCSCCN
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CCSCCSCCNC(=O)NC

Procedure:
6 g of methyl isocyanate in 15 ml of ethyl acetate were added dropwise at room temperature to a solution of 16.5 g of 1-amino-3,6-dithiaoctane in 40 ml of ethylacetate. The urea precipitated was recrystallised twice from methanol/water.