Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][N:3]=1.[NH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:22][CH:19]1[CH2:20][CH2:21][N:17]([C:2]2[N:3]=[CH:4][C:5]([B:8]([OH:9])[OH:12])=[CH:6][CH:7]=2)[CH2:18]1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: OC1CCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: OB(O)c1ccc(N2CCC(O)C2)nc1
Temperature: 180 °C

Procedure:
To a solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (239 mg, 1 mmol) in NMP (2 mL) was added pyrrolidin-3-ol (174 mg, 2 mmol) and DIPEA (500 uL, 3 mmol), then the mixture was sealed in a microwave tube and heated in microwave reactor at 180° C. for 1.5 hours. TLC and LC-Ms showed the reaction had completed and the desired compound was detected. The reaction mixture was poured into 30 mL of H2O, and extracted with n-BuOH, washed with water and brine, concentrated and purified on TLC(CH2Cl2:MeOH=10:1) to give a white solid. MS (m/z): 209 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:17][NH:18][C:19](=[O:22])[CH2:20][Cl:21].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:21][CH2:20][C:19]([NH:18][CH2:17][C:6]1[C:7]([OH:15])=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(O)c(CNC(=O)CCl)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A finely powdered mixture of 5.2 g (25 mmol) of 3,5-di-tert-butylphenol and 3.15 g (25 mmol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 22.5 mL acetic acid and 2.5 mL (98%) sulfuric acid at 0-10° C. The reaction mixture was allowed to warm to room temperature over several hours, and stirring was maintained for a total of 16 hours. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15-30-50% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CCNC(=O)OC(C)(C)C)Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A stirred solution of 1.5 grams (0.0052 mole) of (tert-butoxy)-N-(2-{[(6-chloro(3-pyridyl))methyl]amino}ethyl)carboxamide and 2.3 mL (0.013 mole) of diisopropylethyl amine in about 15 mL of methylene chloride was cooled to 0° C., and 0.7 mL (0.0052 mole) of (4-methoxyphenyl)methyl chloride in about 3 mL of methylene chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature, where it stirred during an 18 hour period. After this time, analysis of the reaction mixture by thin layer chromatography (TLC) indicated that no reaction had taken place. The reaction mixture was then heated at reflux for two hours, after which TLC analysis indicated that no reaction had taken place. The methylene chloride solvent was removed under reduced pressure from the reaction mixture, which was replaced with chloroform. The reaction mixture was heated at reflux during one hour, and then it was allowed to cool to ambient temperature, where it stirred during an 18 hour period. After this time TLC analysis indicated the presence of some reaction product. The reaction mixture was then heated at reflux for about a nine hour period and then it was allowed to cool to ambient temperature as it stirred during an additional 18 hour period. After this time the chloroform solvent was removed under reduced pressure from the reaction mixture, which was replaced with acetonitrile. The reaction mixture was then stirred at ambient temperature during a four hour period, warmed to 60° C. where it stirred for a ten hour period, and finally stirred at ambient temperature during a 60 hour period. The reaction mixture was concentrated under reduced pressure to a residue, and the residue was purified with column chromatography on silica gel. Elution was accomplished using 30% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.6 %

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) in 1,2-dichloroethane (5 mL) was added acetic acid (0.2 mmol), formaldehyde (37% water solution, 0.037 mL), and NaBH(OAc)3 (0.2 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (2 M NH3 in MeOH/CH2Cl2) afforded 0.015 g of the title compound. MS (ESI): exact mass calculated for C21H22ClN3, 351.15. found, m/z 352.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.45-7.42 (m, 2H), 7.32-7.29 (m, 2H), 7.26-7.19 (m, 3H), 7.03-7.01 (br m, 2H), 5.27 (s, 2H), 2.75-2.68 (m, 4H), 2.64-2.58 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][NH2:14].C(O)(=O)C>O>[CH3:12][O:13][N:14]=[CH:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[N:5][C:6]=1[Cl:10]
Reactant: Nc1ncnc(Cl)c1C=O
Reactant: CON
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CON=Cc1c(N)ncnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1a (1.0 g), O-methyl-hydroxylamine hydrochloride (0.94 g) and a mixed solvent of acetic acid (25 mL) and H2O (4 mL) were added to a flask. The mixture was stirred at rt overnight, then concentrated. The residue was suspended in H2O and extracted with EtOAc. The organic layer was separated, dried with MgSO4, then concentrated to afford 4-amino-6-chloro-pyrimidine-5-carbaldehyde O-methyl-oxime Compound 9a (0.97 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.70 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z: 188 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH:21][OH:22])=[NH:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CO[C:27](=O)[CH2:28][N:29]([CH3:31])[CH3:30].[ClH:33]>O1CCCC1.C(O)(C)C>[ClH:33].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:20]=[C:27]([CH2:28][N:29]([CH3:31])[CH3:30])[O:22][N:21]=3)=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CN(C)C
Reactant: COc1cccc2c(C(=N)NO)cn(CC3CCCCC3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1cccc2c(-c3noc(CN(C)C)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Molecular sieves (4 Å, powdered, 200 mg) were added to a suspension of 1-(cyclohexyl)methyl-N-hydroxy-7-methoxy-1H-indole-3-carboxamidine (250 mg, 0.829 mmol) in tetrahydrofuran (6 ml) under nitrogen, and the mixture was stirred at room temperature for 30 min. Sodium hydride (60% suspension in oil, 36 mg, 0.900 mmol) was added, then the resulting mixture was stirred at 60° C. for 20 min. The reaction mixture was cooled to room temperature and N,N-dimethylglycine methyl ester (194 mg, 1.66 mmol) was added to the mixture. The resulting mixture was stirred at reflux temperature for 2 h and then concentrated in vacuo. The obtained residue was mixed with dichloromethane (200 ml), washed with 5% aqueous sodium carbonate, dried over magnesium sulfate and concentrated in vacuo. The obtained oil was purified by flash column chromatography eluting with 0.6% (v/v) methanol in dichloromethane to afford an oil. This oil was dissolved in isopropanol (3 ml), then hydrogen chloride (1M solution in diethyl ether; 3 ml) was added to the solution. The resulting mixture was concentrated in vacuo to afford the title compound (1:1 hydrochloride salt) (66 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]5[CH2:25][CH2:24][CH2:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]([C:44]1C=CC=C[CH:45]=1)(=O)[CH2:40][CH2:41]C>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[S:19][C:20]([CH2:25][CH3:24])=[C:21]([C:23]5[CH:45]=[CH:44][CH:39]=[CH:40][CH:41]=5)[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: CCCC(=O)c1ccccc1
Product: CCc1sc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)nc1-c1ccccc1

Procedure:
The procedure for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert butyrophenone (436 μL, 3.00 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 8.9-11.1 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-4-phenyl-1,3-thiazol-2-amine as a white powder (0.022 g, 0.037 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 9.27 min;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(Cl)Cl.[CH3:14][OH:15]>[Ti](Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:14](=[O:15])[CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: CO
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1)c1c[nH]c2ccc(Br)cc12

Procedure:
To 5-bromoindole (160 g), 1-phenylacetyl-1H-1,2,3-benzotriazole (193.62 g) and methylene chloride (2120 ml) were added, the mixture was stirred under ice cooling while adding a solution of titanium(IV) chloride (179 ml) in a methylene chloride solution (450 ml) and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution, methanol (220 ml) and water (1126 ml) were added, the mixture was stirred at room temperature for 21 hours and in an ice water bath for 3 hours, then the precipitated crystals were obtained by filtration to afford the above-identified compound (163.0 g).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:103]=[CH:102][C:66]([CH2:67][O:68][C:69]([NH:71][C@@H:72]([CH2:95][S:96][S:97][C:98]([CH3:101])([CH3:100])[CH3:99])[C:73]([NH:75][CH2:76][CH2:77][CH2:78][CH2:79][C@H:80]([NH:87][C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])[C:81](OCC#N)=[O:82])=[O:74])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([C:63]1[CH:64]=[CH:65][C:66]([CH2:67][O:68][C:69]([NH:71][C@@H:72]([CH2:95][S:96][S:97][C:98]([CH3:101])([CH3:100])[CH3:99])[C:73]([NH:75][CH2:76][CH2:77][CH2:78][CH2:79][C@@H:80]([NH:87][C:88]([O:90][C:91]([CH3:92])([CH3:93])[CH3:94])=[O:89])[C:81]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:82])=[O:74])=[O:70])=[CH:102][CH:103]=1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 11.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (30.3 mg, 0.048 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk24) (93 mg, 0.143 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (9 mL), and the mixture was stirred at room temperature for 4.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk25) (6.7 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]P(=O)(OC)OC)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].C([N-]C(C)C)(C)C.[Li+].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:47]2[CH2:48][CH2:49][N:44]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:45][CH2:46]2)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COP(=O)(Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude [[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]phosphonic acid, dimethyl ester (2.50 g, Example 50a) in tetrahydrofuran (50 ml) at −78 ° C. was added a solution of lithium diisopropylamide (7.30 ml, 2M in tetrahydrofuran). The reaction was allowed to warm to room temperature and stirred for 15 min. N-t-butoxycarbonylpiperidin-4-one (1.52 g) in tetrahydrofuran (5 ml) was then added and the mixture stirred for 24 h. The reaction was diluted with water and extracted with ethylacetate. The organic layer was washed with brine and dried over magnesium sulfate. The crude material was purified on a silica gel (0 to 5% methanol in dichloromethane) to afford the subtitle compound as a white foam.
Reaction SMILES: [CH2:1]([CH:7](C)[C:8]([NH2:17])([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.F[C:20](F)(F)C(O)=O.N>C(Cl)CCl>[C:13]1([CH3:16])[CH:12]=[CH:11][C:10]([CH:8]2[C:7]3[CH:1]=[CH:2][O:6][C:5]=3[CH2:4][CH:3]([CH3:20])[NH:17]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(N)(O)C(C)Cc2ccco2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: N
Solvent: ClCCCl
Product: Cc1ccc(C2NC(C)Cc3occc32)cc1

Procedure:
Twenty grams (0.08 mol) of 2-furfuryl-2-methyl-amino-1-p-methyl-phenyl-ethanol were dissolved in 100 ml of ethylene chloride and heated to boiling point for three hours with 100 ml of trifluoroacetic acid. The reaction mixture was poured onto ice and neutralized with concentrated ammonia. The organic constituents were extracted with ether. Aftery drying, the ether was distilled off in vacuo. The residue was purified over silica gel [cyclohexane/ethyl acetate (1:1)]. After the solvent was distilled off in vacuo, the residue was dissolved in acetate. After addition of ethereal hydrochloric acid, the hydrochloride of the title compound crystallized out.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:8][S:9]([O:13][CH:14]([CH2:23][CH2:24][O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:11])=[O:10]
Reactant: COC(=O)CCCCC(O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, triethylamine (0.7 ml, 5.05 mmol) and methanesulfonyl chloride (0.3 ml, 3.71 mmol) were added to a solution of (±)-methyl 6,8-dihydroxyoctanoate (320 mg, 1.68 mmol) in dichloromethane (8.4 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, then quenched with ice water (20 ml) and extracted with dichloromethane (20 ml). The organic extract was washed with 2 M hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (2:3) to give (±)-methyl 6,8-bis(methylsulfonyloxy)octanoate (581 mg, 99% yield) as a clear yellow oil. Rf 0.30 (hexane-ethyl acetate, 3:2).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].I[CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].O>CN(C)C=O>[S:1]([CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: O=C1N[C@H](CI)[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CSC[C@H]1NC(=O)[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
1.5 g of potassium thiocyanate were added at 75° C. with stirring to a mixture of 1.78 g of the product of Step A in 5 ml of dimethylformamide and the mixture was stirred for 31/2 hours and was poured into water. The mixture was vacuum filtered and the product was washed with water and dried. The product was empasted with hot isopropyl ether, vacuum filtered and dried to obtain 1.25 g of racemate of cis 4-thiocyanatomethyl-3-phthalimido-2-oxo-azetidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.Br[CH2:11][C:12](=O)[CH3:13].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:5]([CH:4]=1)=[CH:9][C:12]([CH3:13])=[CH:11]2
Reactant: COc1ccnc(C)c1
Reactant: CC(=O)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: COc1ccn2cc(C)cc2c1
Temperature: 0 °C
Yield: 31 %

Procedure:
4-Methoxy-2-methylpyridine (0.123 g, 1 mmol) and bromoacetone (0.16 mL, 1 mmol) were heated at 95° C. under N2 for 2 h. 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (0.34 mL, 2.2 mmol) in benzene (10 mL) was added. The mixture was then refluxed under N2 for 1 h, poured into ice water, and then extracted with EtOAc. The combined organic layers were washed with water and dried. After the solvent was removed in vacuo, the residue was purified on a silica gel column eluting with EtOAc:Hexane (1:9) and EtOAc to give 7-methoxy-2-methylindolizine (0.050 g, 31%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:37]=[C:36]([CH3:38])[C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[C:28]([CH3:39])[CH:27]=1)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH2:24][C:26]2[CH:37]=[C:36]([CH3:38])[C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[C:28]([CH3:39])[CH:27]=2)=[CH:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1c(C)cc(C=O)cc1C
Reactant: Clc1ccc2ccn(C(c3ccccc3)c3ccccc3)c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cc2cn(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc(C)c1OCC(=O)O
Temperature: 0 °C
Yield: 89 %

Procedure:
To 1-benzhydryl-6-chloro-1H-indole (1.0 eq) and methyl 2-(4-formyl-2,6-dimethylphenoxy)acetate (0.6 eq) in CH2Cl2 (0.1M) at 0° C. was added neat triethysilane (3 eq) followed by triflouroacetic acid (3 eq). After 10 minutes at 0° C. the reaction was warmed to room temperature and stirred until the initially formed spot by TLC yields a new spot. The reaction was then quenched by the addition of saturated sodium bicarbonate, diluted with CH2Cl2 and washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and purified by column chromatography to yield 89% of the desired product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CN(C=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 73.2 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 3-amino-3-phenyl-propionic acid (257 mg, 1.56 mmol) (Sigma-Aldrich) in 3 mL of DMF was added NaOMe solid (67 mg, 1.25 mmol). The resultant mixture was heated in a 150° C. oil bath for 3 h. After cooled, insoluble was filtered off. Filtrate was diluted with water (100 mL). This suspension mixture was brought to clear by adding 1 N NaOH (pH=ca. 10). It was then acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound 103 mg (0.227 mmol) in 73% yield. LC-MS ESI−: 451.95 (M−1)−.