Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].CS(OS(C)(=O)=O)(=O)=O.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:37][CH2:38][CH3:39])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:23]=2[C:22]2[CH:21]=[CH:20][C:19]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[CH:18][C:17]=2[N:16]=1.CO>ClCCl>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:37][CH2:38][CH3:39])[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:23]=2[C:22]2[CH:21]=[CH:20][C:19]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:1](=[O:3])[CH3:2])=[CH:18][C:17]=2[N:16]=1
Reactant: CCCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CCCCNS(C)(=O)=O
Reactant: CC(=O)Cl
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CO
Product: CCCc1nc2c(N)nc3cc(OCCCCCCNC(C)=O)ccc3c2n1CCCCNS(C)(=O)=O
Yield: 33.1 %

Procedure:
A modification of the method described in Park K of Example 45 was followed using acetyl chloride (135 μL, 1.91 mmol) in lieu of methanesulfonic anhydride and N-{4-[4-amino-7-(6-aminohexyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide (0.85 g, 1.7 mmol) as the starting material. The crude product was purified by column chromatography on silica gel (eluting sequentially with 90:10 and 80:20 dichloromethane:methanol). The resulting white powder was stirred with water, isolated by filtration, and dissolved in 50:50 dichloromethane:methanol. The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and further dried overnight under high vacuum at 60° C. to provide 0.30 g of N-(6-{4-amino-1-[4-(methanesulfonylamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy}hexyl)acetamide as a white powder, mp 168-172° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([OH:23])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.F[C:25](F)(F)C(O)=O>CO>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([O:23][CH3:25])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3OC(O)[C@H](O)[C@@H]3O)c21
Solvent: CO
Product: COC1O[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
To a solution of 4-Amino-5-(((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (Example 265a) (7 mg, 0.020 mmol) in dry methanol (1 mL) was added trifluoroacetic acid 0.2 mL) and the mixture was refluxed overnight. The resulting solution was evaporated to dryness to provide the title compound as a white powder (7.28 mg, 100%, mixture of diastereomers ˜4/1). 1H NMR (400 MHz, DMSO-d6): δ [3.17 (s, ¾H)], 3.22 (s, 3H), 3.81 (d, J=4.0 Hz, 1H), [3.93 (m, ½H)], 4.12 (m, 3H), 4.39 (m, 1H), 4.71 (s, 1H), [4.85 (d, J=4.0 Hz, ¼H)], 5.44 (br s, 2H), 6.65 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.95 (s, 1H), 8.41 (s, 1H), 11.00 (s, 1H), [11.01 (s, ¼H)].
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[N:6]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:5]2[N:6]=[C:2]([CH3:1])[N:3]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:4]=2)=[O:42])=[CH:36][CH:35]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1nc(-c2sccc2N)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(C)n2)cc1

Procedure:
The title compound was prepared from 2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B (540 mg, 57%). Method [7] Retention time 7.42 min by HPLC (MH+ 570).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[N:22]=[C:21]2[CH3:34])=[CH:16][CH:15]=1.CI>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH3:1])=[C:23]([C:25]#[C:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[N:22]=[C:21]2[CH3:34])=[CH:16][CH:15]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C#Cc2nc(C)n(-c3ccc(F)cc3)c2C)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (0.260 mg, 2.6 mmol) was dissolved in 5 mL dry tetrahydrofurane, n-butyllithium (1.6 mL, 1.6 M in hexane, 2.6 mmol) were added at −78° C. and the mixture was kept at −78° C. for 10 min. 4-[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridine (1) (500 mg, 1.72 mmol) in 5 mL dry tetrahydrofurane was added at −78° C. and stirring was continued for 45 min at this temperature. Methyl iodide (410 mg, 2.9 mmol) was added at −78° C. and the reaction mixture was slowly warmed to RT. The reaction mixture was quenched by addition of 50 mL water and extracted three times with diethylether (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (methylenchloride/methanol 9:1) and the desired compound was obtained as a white solid (325 mg, 62%), MS: m/e=306.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[C:5]([CH:12]2[CH2:14][O:13]2)=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH2:28][OH:29])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C>[C:8]([C:7]1[C:6]([O:10][CH3:11])=[C:5]([CH:12]([OH:13])[CH2:14][N:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:23][C@H:24]2[CH2:28][OH:29])[CH:4]=[CH:3][C:2]=1[F:1])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: COc1c(C2CO2)ccc(F)c1C#N
Solvent: CCO
Product: COc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Temperature: 150 °C

Procedure:
6-Fluoro-2-methoxy-3-(oxiran-2-yl)benzonitrile (1.4 g, 7.3 mmol) and (S)-4-N-BOC-2-hydroxymethylpiperazine (3.13 g, 14.5 mmol) were suspended in ethanol (15 mL) then heated in a microwave apparatus for 60 min at 150° C. The reaction mixture was cooled and evaporated to dryness. The residue was purified by chromatography through a 40 g Redi-sep column and eluting with 5% MeOH/95% EtOAc to yield the title compound: LC-MS: M+1=410;
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.BrC1C=CC(S(O[CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)(=O)=O)=CC=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2cccc(C)c2C)CC1)O3
Temperature: 70 °C
Yield: 89.9 %

Procedure:
A mixture of 1-(2,3-dimethylphenyl)-piperazine (1.13 g, 5.94 mmol) and [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzene-sulfonate (871 mg, 1.93 mmol) in anhydrous DMSO (10 mL) was heated overnight at 70° C. The reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (50% EtOAc/hexanes) afforded 700 mg (90%) of the title compound as a white solid: mp 112–113° C.; MS (ESI) m/z 404 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27]2)[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNC4)nc3-c3ccc(F)cc3F)nn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nnc2ccc(-c3cn(C4CCN(S(C)(=O)=O)C4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
To a round bottom flask was added 6-(3-(2,4-difluorophenyl)-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.105 g, 0.256 mmol, Example #Q.1.1.1), DCM (5 mL) and DIPEA (0.054 mL, 0.31 mmol). Then methanesulfonyl chloride (0.020 mL, 0.26 mmol) was added. The reaction mixture was stirred at ambient temperature for about 10 min. The reaction mixture was purified directly by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 9:1) to give the title compound (0.120 g, 96%): LC/MS (Table 1, Method g) Rt=2.28 min; MS m/z: 488.3 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.C(O)C.[C].[Pd]>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(/C=C/c2c(C(N)=O)cnn2C(C)(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCc2c(C(N)=O)cnn2C(C)(C)C)cc1
Yield: 98.1 %

Procedure:
A mixed solution of the compound (80 mg, 0.27 mmol) obtained in step 1, 10% palladium carbon (28.4 mg, 0.27 mmol) in THF (15 mL) and ethanol (15 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 6 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 1-tert-butyl-5-(4-methoxyphenethyl)-1H-pyrazole-4-carboxamide (80 mg, 0.265 mmol, 99%) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17].O>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1nn[nH]c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)c1nn[nH]c1NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Benzoyl chloride (28 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-4-carbamoyl-1H-1,2,3-triazole (15.24 g.) in anhydrous pyridine (240 ml.), and the reaction mixture was then stirred at room temperature for 40 hours. The mixture was poured into cold water (1,200 ml.), and the solid filtered off and washed well with water. The crude solid was heated in a large volume of boiling ethanol, and the insoluble material filtered off while still hot, to give 5-benzamido-4-carbamoyl-1H-1,2,3-triazole (20.4 g.), m.p. 301° C. (with decomposition).
Reaction SMILES: [P:1]([Cl:15])(Cl)([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].Cl.[CH2:17]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH3:18].CCN(CC)CC>C(Cl)Cl>[Cl:15][P:1]([NH:22][C@H:21]([C:20]([O:19][CH2:17][CH3:18])=[O:24])[CH3:23])([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cccc2ccccc12

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.144 M) of 1-naphthyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1.1* mixture of diastereoisomers. 31P NMR (300 MHz, CDCl3) δ: 9.47 and 9.14*.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:12]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])Cl)([CH3:14])[CH3:13].[NH4+].[Cl-].CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2
Reactant: Fc1cc(F)c2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cc(F)c21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
N-butyl lithium (2.7 ml, 2.5 M, 6.9 mmol) was added to 10 mL dry THF at −70° C. 5,7-difluoro-1H-indole (1.0 g, 6.5 mmol) in 5 mL THF was added in portions to the this solution and the mixture was stirred for 30 min at −75° C. Triisopropylchlorosilane (1.5 mL, 1.3 g, 6.9 mmol) was added, stirring was continued for 1 h at −75° C. and then the mixture was allowed to warm to −5° C. over 2 h. After treatment with 5 mL sat. NH4Cl, the mixture was mixed with 30 mL ether and the organic phase was washed with 5 mL sat. NaCl, dried (Na2SO4) and evaporated. The product was purified by flash chromatography (SiO2; hexanes) to provide the title compound as a clear oil (1.5 g; 74%): 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=3.1 Hz, 1H), 7.07 (dd, J=8.7, 2.3 Hz, 1H), 6.69 (m, 1H), 6.59 (t, J=3.1 Hz, 1H), 1.67 (m, 3H), 1.13 (d, J=7.6 Hz, 18H). 19F NMR (376 MHz, CDCl3) δ −120.64, −120.65, −122.49, −122.49. EIMS m/z 309.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CN(C1CCCCC1)C1CCCCC1.[CH3:27][O:28][CH2:29]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:27][O:28][CH2:29][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([CH3:1])=[CH:3][C:4]([CH:11]=[O:12])=[CH:5]2)=[N:9]1
Reactant: COCCl
Reactant: Cc1cc(C=O)cc2cn[nH]c12
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1cc2cc(C=O)cc(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 7-methylindazole-5-carboxaldehyde (8.80 g, 54.9 mmol) and N-methyl-dicyclohexylamine (23.6 mL, 110 mmol) in tetrahydrofuran (200 mL) at 0° C. was added chloromethyl methyl ether (7.50 mL, 1.8 equiv). The reaction was allowed to gradually warm to room temperature overnight. The reaction was concentrated, dissolved in diethyl ether, washed with water, then 1 M hydrochloric acid, then water, then brine, dried over magnesium sulfate, and concentrated to give an oil. The oil was dissolved in ethyl acetate and treated with hexanes until lasting turbidity. The suspension was heated until a clear solution was obtained and the flask placed in the freezer. The resulting crystalline solid was crushed with a spatula to break it up, reheated to dissolve some of the solids, and placed in the freezer. The solids were filtered, washed with very cold ether (−78° C.), and air-dried to give 5.43 g. The mother liquor was concentrated, redissolved in ca. 20 mL ether, cooled to −78° C., and treated with a seed crystal of the product. After 1 h, the resulting solids were filtered, washed with cold ether (−78° C.), and air-dried to give an additional 1.05 g (total yield=58%). 1H-NMR (CDCl3, 500 MHz) δ 2.66 (s, 3H), 3.44 (s, 3H), 5.73 (s, 2H), 7.59 (s, 1H), 8.09 (s, 1H), 8.32 (s, 1H), 9.97 (s, 1H). Mass spec.: 205.19 (MH)+.
Reaction SMILES: C(O[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.[CH:21]([NH2:24])([CH3:23])[CH3:22].C([BH3-])#N.[Na+]>C(Cl)CCl.CO.[Ti](Cl)(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:4](=[O:20])[N:24]([CH:21]([CH3:23])[CH3:22])[CH:12]2[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CC(C)N1C(=O)c2ccc(Br)cc2C1c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Benzoyl-4-bromo-benzoic acid ethyl ester (50 mg; 0.15 mmol) is dissolved in ethylene dichloride (1 ml) and treated with 1 mol/l Titanium(IV)chloride solution (150 μl; 0.15 mmol) and cooled down to 0° C. Isopropylamine (13 μl; 0.15 mmol) is added and stirred for 2 hours at ambient temperature and 16 hours at 80° C. A 6.5 mol/l solution of sodium cyano borohydride in methanol (140 μl; 0.90 mmol) is added and stirred for 3 days followed by another portion of sodium cyano borohydride in methanol and 16 hours at 50° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([NH:15][C@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[N:8]=2>CO>[CH3:20][C@@H:16]([NH:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([O:2][CH3:1])[N:6]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:11]([NH2:14])[N:10]=1)[CH2:17][CH2:18][CH3:19]
Reactant: C[O-]
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium methoxide in methanol (0.5M, 9 ml, 4.5 mmol) was added to a solution of 8-bromo-N2-[(1R)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (0.844 g, 2.20 mmol) in methanol (12 ml) and the resulting solution heated under reflux for 23.5 hours. More sodium methoxide in methanol (0.5M, 4.5 ml) was then added and refluxing continued for a further 4 hours. More sodium methoxide in methanol (0.5M, 4.5 ml) was again added and refluxing continued for a further 16.5 hours when LCMS indicated reaction to be complete. The reaction mixture was cooled to room temperature, evaporated and the residue partitioned between ethyl acetate (75 ml) and water (75 ml). The aqueous phase was re-extracted with ethyl acetate (75 ml) and the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on a 100 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 15 mins. Product-containing fractions were combined and evaporated in vacuo to give the title compound as a white foam (0.614 g).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5](OCCC)=[CH:4][CH:3]=1.[CH:21](C1C2SC3C(=CC=CC=3)C(=O)C=2C=CC=1)([CH3:23])[CH3:22]>>[CH:21]([C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1cccc2c(=O)c3ccccc3sc12
Reactant: CCCOc1ccc(Cl)c2c(=O)c3ccccc3sc12
Product: CC(C)c1ccc2sc3ccccc3c(=O)c2c1

Procedure:
1-chloro-4-propoxythioxanthone; 4-isopropylthioxanthone; and the mixture thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]=[O:13].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][OH:13])[C:6](=[O:11])[CH2:5]2
Reactant: C=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1Cc2cc(Cl)ccc2N1CO
Temperature: 25 °C

Procedure:
In an high pressure autoclave, 5-chloro-1,3-dihydro-indol-2-one (5 g, 0.029 mol), paraformaldehyde (1.07 g) and toluene (60 ml) are heated up to 120° C. for 4 h. The mixture is cooled down to room temperature, diluted with ether and filtrated to give 5-chloro-1-hydroxymethyl-1,3-dihydro-indol-2-one a22 as white crystals (4.03 g, 70%). 1H NMR δH (250 MHz, C2D6SO): 3.61 (2H, s); 5.04 (2H, d); 6.26 (1H, t); 7.08 (1H, d); 7.29-7.34 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:26][CH:27]=2)=[O:14])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCOc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCOc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
4-(benzyloxy)benzoic acid (20.0 g, 87.6 mmol), 4-(hexyloxy)phenol (17.0 g, 87.6 mmol), N,N′-dicyclohexylcarbodiimide (21.7 g, 105 mmol) and 4-dimethylaminopyridine (535 mg, 4.38 mmol) were dissolved in 300 mL of methylene chloride. The resulting solution was stirred for 3 hours at room temperature. Then, 300 mL of pure water was added thereto, and then the resulting liquid was filtered to remove insoluble matters. Thereafter, the obtained solution was subjected to separation operation, and the resulting methylene chloride solution was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After methylene chloride was distilled off, the resulting solid matter was washed with methanol. Thereby, a white solid compound, 4-(hexyloxy)phenyl 4-(benzyloxy)benzoate (24.9 g) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:21].O[CH2:26][CH2:27][CH2:28][N:29]([CH3:49])[C:30]([C:32]1[N:33]([CH3:48])[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]2[C:40]=1[CH:39]=[CH:38][C:37]([Cl:41])=[CH:36]2)=[O:31]>O1CCOCC1>[Cl:21][CH2:26][CH2:27][CH2:28][N:29]([CH3:49])[C:30]([C:32]1[N:33]([CH3:48])[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]2[C:40]=1[CH:39]=[CH:38][C:37]([Cl:41])=[CH:36]2)=[O:31]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CN(CCCO)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(CCCCl)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C

Procedure:
A solution of 13.6 g. of triphenylphosphine in 40 ml. of carbon tetrachloride and 24 ml. of dioxane is treated with 14.3 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-hydroxypropyl)methylamide and the mixture is subsequently boiled at reflux for 1 hour. After cooling, the mixture is concentrated to dryness under reduced pressure. The residual oil is chromatographed on 800 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The homogeneous fractions yield analytically pure 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-chloropropyl)methylamide as a thick yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:7][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[OH:9])[CH3:3].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>C(OCC)C>[C:26]([O:9][CH:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:14][CH2:13]2)[CH2:7][O:6][CH2:5][CH2:4][N:2]([CH3:1])[CH3:3])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOCC(O)c1ccc2c(c1)CCC2OC1CCCCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.5 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethanol, 8 ml of acetic anhydride and 0.64 ml of pyridine was stirred at room temperature for 1 hour. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=10/1) to obtain 1.9 g of oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-[1-(tetrahydropyran-2-yloxy)indan-5-yl]ethane (compound No. 295).