Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.CN([CH:17]=[O:18])C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:17]=[O:18])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cccc2c(C)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c2c(C)cccc12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a well stirred solution of 1-methoxy-5-methylnaphthalene (above Step-3 intermediate) (7.0 g, 40.7 mmol) in toluene (8 mL) and DMF (4.7 mL, 61 mmol) at 0° C. was added, POCl3 (4.6 mL, 49.6 mmol) drop wise and the reaction mixture was stirred for 45 min at 0° C. and then refluxed for 2 h. The dark red solution was cooled to RT and poured into a mixture of ice (50 mL) and 10% aq. NaOH (100 mL) with stirring. The crude product was extracted with EtOAc (4×75 mL) and the combined organic layer was washed with 1 N HCl (3×50 mL), water (3×50 mL), brine, dried (Na2SO4) and filtered. The solvent was evaporated and the residue was washed with hexanes (2×15 mL) to afford the desired compound (6.4 g, 79%) as reddish brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:36]#[N:37]>CN(C)C=O>[C:36]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[O:1][C:2]1[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)#[N:37]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A resealable tube was charged with 6-hydroxy-1-naphthoic acid (0.596 g, 3.17 mmol), cesium carbonate (3.10 g, 9.51 mmol), and N,N-dimethylformamide (15 mL, Aldrich). The system was flushed with argon, the tube was sealed, and the mixture stirred at RT for 15 min. A solution of 4-chloro-3-cyano-6,7-dimethoxyquinoline (0.788 g, 3.17 mmol) in N,N-dimethylformamide (10 mL) was added (along with a 5 mL DMF rinse), and the system was again flushed with argon. The tube was sealed and the mixture stirred at 60° C. for 2 h. The mixture was diluted with water (30 mL) and 6 N HCl (aq) was added dropwise with stirring until the pH of the solution was 6-7. The resulting precipitate was filtered and washed with water. The filter cake was dried under vacuum to afford 6-(3-cyano-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid as a light brown solid. MS (ESI, pos. ion) m/z: 401.0 (M+H). Mass Calc'd for C23H16N2O5: 400.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH:16]=[C:15]([C:22](O)=[O:23])[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:7][CH2:6]1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[CH3:54][C:55]([NH2:58])([CH3:57])[CH3:56].C(N(C(C)C)CC)(C)C>CCOC(C)=O>[C:55]([NH:58][C:22]([C:15]1[N:14]=[C:13]([C:11]2[CH:10]=[N:9][N:8]([CH:4]([CH:5]3[CH2:6][CH2:7]3)[CH2:3][C:1]#[N:2])[CH:12]=2)[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=1)=[O:23])([CH3:57])([CH3:56])[CH3:54]
Reactant: CC(C)(C)N
Reactant: N#CCC(C1CC1)n1cc(-c2nc(C(=O)O)cc3nccn23)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cc2nccn2c(-c2cnn(C(CC#N)C3CC3)c2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
In a 2 mL flask, 5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylic acid (6.5 mg, 0.020 mmol) and HATU (9.2 mg, 0.024 mmol) were dissolved in DMF (101 μL, 0.020 mmol). After 5 minutes, 2-methylpropan-2-amine (4.4 mg, 0.061 mmol) and diisopropylethylamine (11 μL, 0.061 mmol) were added and the reaction mixture stirred at ambient temperature for 45 minutes. The reaction mixture was diluted in EtOAc and washed with water, saturated sodium bicarbonate, water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC using a gradient of 40-100% acetonitrile/water to afford N-tert-butyl-5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxamide (1.0 mg, 0.0026 mmol, 13% yield). MS (apci) m/z=378.3 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])=[CH:16][CH:15]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:9]([O:8][CH2:7][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: C=CCCCCCCOc1ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCOc1ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Reaction time: 6 h
Yield: 92.5 %

Procedure:
10% Palladium carbon (0.1 g) was added to a solution (30 ml) of 2-acetamido-2-[2-{4-(7-octenyloxy)phenyl}ethyl]-1,3-propanediol diacetate (1.27 g) in ethanol and the mixture was stirred at ordinary temperature and at atmospheric pressure for 6 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated. The residue was collected by filtration to give the subject compound (1.18 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[N:3]1.[Br:19]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg, 2.70 mmol) [prepared in Example 112] and N-bromosuccinimide (481 mg, 2.70 mmol) in tetrahydrofuran (12 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (2.251 ml, 13.51 mmol). The reaction mixture stirred at 70° C. in a sealed tube for 12 h and was partitioned between H2O-DCM. The pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (445 mg, 1.35 mmol, 50% yield): LCMS (ES) m/e 329, 331 (M, M+2)+.
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:95]=[CH:94][CH:93]=[CH:92][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][C@@H:71]([S:89][S:90][CH3:91])[CH2:72][CH2:73][C@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75](OCC#N)=[O:76])=[O:68])=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:95]=[CH:94][CH:93]=[CH:92][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][C@H:71]([S:89][S:90][CH3:91])[CH2:72][CH2:73][C@@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[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][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:76])=[O:68])=[N+:61]=[N-:62]
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
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CSS[C@H](CC[C@@H](NC(=O)OC(C)(C)C)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)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 5.2 %

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) and (2S,5S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk16) (77 mg, 0.143 mmol) in acetonitrile (0.7 mL) was added to buffer A (8 mL), and the mixture was stirred at room temperature for 40 minutes. Acetonitrile (3 mL) was added, followed by stirring for 55 minutes. Acetonitrile (2 mL) was further added, followed by stirring for 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,5S)-(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-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk17) (2.8 mg, 5%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([O:19][CH3:20])=[CH:12][C:11]=1[CH3:21])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([O:19][CH3:20])=[CH:12][C:11]=1[CH3:21])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(CCCCl)c1cc(C(C)C)c(OC)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c(C(CCCCl)C(=O)O)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Methyl 5-chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoate (7.7 g) was dissolved in a mixed solvent of methanol (25 mL) and tetrahydrofuran (25 mL). A 5 N sodium hydroxide solution (22 mL) was added and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure and water was added, followed by washing with heptane. The aqueous layer was made acidic with 5 N hydrochloric acid, followed by extraction with tert-butyl methyl ether. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the organic layer was concentrated under reduced pressure to obtain 5-chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid (6.2 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2nc3c(O)cccc3s2)cc1
Product: CC(=O)Oc1cccc2sc(-c3ccc(C)cc3)nc12

Procedure:
The 4-hydroxy-2-(4-methylphenyl)benzothiazole (5.8 g) obtained in Example 1 was added to 58 ml of acetic anhydride and refluxed for 3 hours. After the reaction, the reaction mixture was dried under reduced pressure. The residue was washed with a small amount of cyclohexane, and recrystallized from cyclohexane to give 4.8 g of 4-acetoxy-2-(4-methylphenyl)benzothiazole.
Reaction SMILES: [C:1]1([OH:9])[CH:8]=[C:6]([CH3:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C.ClCCl>C(OCC)C>[CH3:7][C:6]1[CH:8]=[C:1]([O:9][S:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:28])=[O:27])[CH:2]=[C:3]([OH:4])[CH:5]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1cc(O)cc(O)c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(O)cc(OS(=O)(=O)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2.0 g (16.1 mmol) of orcinol in diethyl ether (100 mL) containing 10 mL of N,N-diisopropylethylamine was added in a slow steady stream 3.05 g (16 mmol) of α-toluenesulfonyl chloride in a solution of 1:1 diethyl ether/dichloromethane (ca. 30 mL). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 10% hydrochloric acid, extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (dichloromethane/diethyl ether (100:0 to 95:5 to 90:10)) to give 848 mg of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.37-7.48 (m, 5H), 6.56-6.57 (m, 1H), 6.51-6.52 (m, 1H), 6.43 (t, 1H, J=2 Hz), 5.21 (s, 1H), 4.50 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[CH2:1]([N:7]([CH2:8][CH:9]1[O:10][CH2:11][CH2:12][O:13]1)[C:28](=[O:29])[CH2:27][Cl:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Hexyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.0 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5.0 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-hexyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [Br:1][C:2]1[C:21]([F:22])=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[CH3:23][C:24]1([CH3:38])[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][P:27]([OH:37])(=[O:28])[O:26][CH2:25]1>C(Cl)Cl.CC(O)C>[OH:37][P:27]1(=[O:28])[O:29][C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]([CH3:23])([CH3:38])[CH2:25][O:26]1.[Br:1][C:2]1[C:21]([F:22])=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CC1(C)COP(=O)(O)O[C@@H]1c1ccccc1
Agent: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)COP(=O)(O)O[C@H]1c1ccccc1
Temperature: 86 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-(cis)-7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-amine (18.58 g, 51.18 mmol) in 300 mL of CH2Cl2 and 60 mL of 2-propanol at 50° C. was added a warm solution of (+)-phencyphos (6.19, 25.59 mmol) in CH2Cl2 (300 mL) and 2-propanol (75 mL). The mixture was heated at 86° C. About 500 mL of CH2Cl2 was removed by careful evaporation, and 310 mL of 2-propanol was added; the mixture was then further concentrated until a final weight of ca. 250 g, and then gradually cooled down to 35° C. After 1 h, the formed crystals were collected by filtration, washed with 2-propanol and dried to yield 12.7 g of crude product (e.e. =95%). This compound was further recrystallized from methanol:CH2Cl2:2-propanol (7:5:2) to give the title compound (12.3 g, 39%, e.e.=99.8%).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=O)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1.[CH3:26][CH2:27][O-].[Na+]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[O:18][N:10]=[C:2]([C:26]4[CH:27]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:3]=3)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1
Reactant: CC[O-]
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OC)c(=O)c2[nH]c(Cl)nc21
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCCc2nc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 41 %

Procedure:
A mixture of methyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (50 mg, 0.13 mmol), benzamidine oxime (20 mg, 0.15 mmol) and a 21% solution of NaOEt in EtOH (76 μl, 0.20 mmol) in EtOH (1.5 ml) was heated in the microwave at 140° C. for 10 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, dried (MgSO4) and concentrated. Purification by the MDAP gave the title compound as a white solid (25 mg, 41%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[CH2:3][CH2:2]1.Br[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][CH2:19][OH:20])[CH2:6][CH2:5]3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1
Reactant: OCCBr
Reactant: c1cc2[nH]ncc2cc1OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 17 h
Yield: 37.5 %

Procedure:
To a solution of the 5-(piperidin-4-yloxy)-1H-indazole (31 mg, 0.143 mmol) obtained in Example 42 in N,N-dimethylformamide (1 ml) were added 2-bromoethanol (0.0121 ml, 0.171 mmol) and potassium carbonate (49 mg, 0.357 mmol). After 17 hours, 2-bromoethanol (0.0121 ml, 0.171 mmol) was further added thereto. After another 24 hours, the reaction mixture was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol/(1%-aqueous ammonia)) to obtain 2-[4-(1H-indazol-5-yloxy)piperidin-1-yl]ethanol (14 mg, 38%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36]COC)[CH:31]=[CH:30][C:29]=4[F:40])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:44][O:45][CH2:46][CH2:47]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:47][CH2:46][O:45][CH3:44])[CH:31]=[CH:30][C:29]=4[F:40])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9]
Reactant: COCCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCCOC)ccc4F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCCCOC)ccc4F)cc23)CC1
Yield: 64.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-(methyloxy)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 3-(methyloxy)-1-propanamine (53 μL, 0.524 mmol) for 2-(methyloxy)ethanamine to afford 15 mg of the title compound (64.5%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=O)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:16]=2)[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:16]=2)[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cccc(N2CC(C)(C)N(C(=O)OC(C)(C)C)CC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
3.47 ml of a borane-tetrahydrofuran complex (1.2 mol/l) (4.16 mmol) was added to a solution of 456 mg of 4-[3-(3-methoxypropoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in the above reaction (1.16 mmol) in tetrahydrofuran (4.16 ml) under a nitrogen atmosphere and under ice-cooling over five minutes, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled in an ice bath. Then, 4.16 ml of a 1 N sodium hydroxide aqueous solution (4.16 mmol) was slowly added and the mixture was further stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=30/1-10/1) to obtain 370 mg of the title compound (yield: 82%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5CC5)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18](OC)=[O:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClCCl.CC(C[AlH]CC(C)C)C.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][OH:19])[CH2:9][CH2:10][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCC1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask containing methyl 8-(4-bromophenyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (5.30 g, 14.92 mmol) was added anhydrous dichloromethane (60 ml) at room temperature. The content was then cool to −78° C. under a dry ice-acetone bath and DIBAL-H (31.1 ml, 37.30 mmol) in toluene was added dropwise slowly. When the addition was completed, the mixture was stirred at −78° C. for 30 minutes or until the consumption of the starting material as indicated by thin layer chromatography (TLC). The reaction was then quenched by the slow addition of a pH 8 buffered solution (prepared by mixing 0.53 mL ammonium hydroxide solution and 8.8 mL of saturated ammonium chloride solution) at −78° C. The mixture was then allowed to warm back up to room temperature and stirred for a further 45 minutes. Solid magnesium sulfate (8 g) was added and the mixture stirred at room temperature for another 30 minutes to afford free flowing slurry. The content was filtered and concentrated to afford the title compound as clear oil, which was used in the next step without purification (4.88 g). LC/MS, ESI-MS: non-ionizable, RT: 1.05 (Condition E).